Podcasts about mptp

Actor Saoirse Ronan recently revealed that she is halfway through writing a short film that she plans to direct— and it feels so relatable. It reminds us that creative struggles are universal, no matter who you are. But being halfway through is not a failure but a part of the journey. Tune in to know what to do to reach the finish line. In today's episode, No Film School's GG Hawkins, Jason Hellerman and guest Patrick Walsh discuss: Saoirse Ronan is halfway through writing a short film she plans to direct  The relatable struggle of getting stuck halfway through a project Outlining and having a clear ending in mind to avoid getting stuck in the middle of a writing project Actors transitioning to directing and the unique perspective they bring The value of grants, labs, and workshops for filmmakers to get support and feedback The list of grants and labs that No Film School has launched on its website The recent positive performance of films at the box office Patrick's journey into editing, starting from film studies Patrick's experience of destination editing for the film The Uninvited Technical challenges and workflow of remote editing Memorable Quotes “I do think short films are coming back to Hollywood.” [03:03]  “Don't start writing something you don't absolutely know how it ends. It's not worth cranking out 100 final draft pages if you don't know what happens in the last four.” [3:39]   “Labs beget labs, just as festivals beget festivals.” [15:50] “These grants are that stepping stone that maybe you didn't know you needed.” [15:03] “Seeing these movies do well has been a strong indicator that movies are back, and original ideas with strong genres and points of view have a viable place in the marketplace.” [21:49]  “It's been good to see Hollywood bounce back a little bit from the strikes and from the MPTP not paying writers and actors what they deserve.” [23:22]  “Films aren't finished. They're abandoned.” [51:33] Links: Patrick Walsh Website  Follow Patrick Walsh on IG Grants and Labs List   Find No Film School everywhere: On the Web https://nofilmschool.com/ Facebook  https://www.facebook.com/nofilmschool Twitter  https://twitter.com/nofilmschool YouTube  https://www.youtube.com/user/nofilmschool Instagram https://www.instagram.com/nofilmschool Send us an email with questions or feedback: podcast@nofilmschool.com! Learn more about your ad choices. Visit megaphone.fm/adchoices

In this episode, we explore the intricate structure and functions of mitochondria, focusing on the electron transport chain complexes and the generation of reactive oxygen species. We delve into the significance of lipid composition in maintaining mitochondrial integrity, the detrimental effects of ROS-induced lipid peroxidation, and how SS-31 can prevent this damage. Additionally, we discuss the potential therapeutic implications of SS-31 peptide not only on the cellular level in mitigating mitochondrial dysfunction, but also its role in various disease settings and exercise capacity as well. Topics: 1. Overview of Mitochondrial Structure - Outer membrane and inner membrane with cristae - Mitochondrial matrix containing DNA, ribosomes, and enzymes - Inner membrane with electron transport chain complexes (I to IV) and ATP synthase 2. Functions of Electron Transport Chain Complexes - Complex I (NADH Dehydrogenase) transferring electrons from NADH to ubiquinone - Complex II (Succinate Dehydrogenase) transferring electrons from FADH2 to coenzyme Q - Complex III (Cytochrome bc1 Complex) passing electrons to cytochrome c and pumping protons - Complex IV (Cytochrome c Oxidase) transferring electrons to oxygen to form water and pumping protons 3. Role of Electron Transfer in ATP Synthesis - Proton pumping by complexes I, III, and IV creating an electrochemical gradient - ATP synthase utilizing proton gradient to synthesize ATP from ADP and Pi 4. Generation and Effects of Reactive Oxygen Species (ROS) - Formation of ROS as byproducts of ATP production - Types of ROS and their damaging effects on cellular components 5. Causes of ROS Production and Mitochondrial Dysfunction - Electron leak leading to premature electron reactions with oxygen - Factors contributing to increased ROS production such as environmental toxins and diet --- Leela Quantum Tech --- 6. Importance of Lipid Composition in Mitochondrial Membrane - Phospholipids, particularly cardiolipin, in the inner mitochondrial membrane - Role of cardiolipin in maintaining membrane integrity and supporting respiration proteins 7. Impact of ROS and Lipid Peroxidation on Mitochondrial Function - ROS-induced lipid peroxidation affecting cardiolipin composition - Implications of cardiolipin peroxidation in diseases like metabolic dysfunction and insulin resistance 8. SS-31 Peptide Intro - Accumulation in the inner mitochondrial membrane - Dimethyltyrosine residue scavenging oxyradicals and inhibiting lipid peroxidation 9. Mechanisms of Action of SS-31 Peptide - Stabilization of lipid constructs in the inner mitochondrial membrane - Prevention of mitochondrial permeability transition pore (mPTP) opening - Reduction of mitochondrial ROS and prevention of mitochondrial swelling and cell death 10. Applications and Research Areas of SS-31 Peptide - Studies in neuroinflammation, neurodegeneration, diabetes, age-related diseases, kidney disease, and cardiac function - Potential as a therapeutic agent for diseases associated with mitochondrial dysfunction 11. Conclusion - Overview of SS-31 peptide's mechanisms and potential applications - Reminder to always consult licensed medical professionals. Thanks for tuning in! Leela Quantum Tech Get Chloe's Book Today! "⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠75 Gut-Healing Strategies & Biohacks⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠" Follow Chloe on Instagram ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠@synthesisofwellness⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ Follow Chloe on TikTok @chloe_c_porter Visit ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠synthesisofwellness.com⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ to purchase products, subscribe to our mailing list, and more! Thanks again for tuning in! --- Support this podcast: https://podcasters.spotify.com/pod/show/chloe-porter6/support

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.21.550097v1?rss=1 Authors: Chang, N. P., DaPrano, E. M., Evans, W. R., Nissenbaum, M., McCourt, M., Alzate, D., Lindman, M., Chou, T.-W., Atkins, C., Kusnecov, A. W., Huda, R., Daniels, B. P. Abstract: Astrocyte activation is a common feature of neurodegenerative diseases. However, the ways in which dying neurons influence the activity of astrocytes is poorly understood. RIPK3 signaling has recently been described as a key regulator of neuroinflammation, but whether this kinase mediates astrocytic responsiveness to neuronal death has not yet been studied. Here, we used the MPTP model of Parkinson's disease to show that activation of astrocytic RIPK3 drives dopaminergic cell death and axon damage. Transcriptomic profiling revealed that astrocytic RIPK3 promoted gene expression associated with neuroinflammation and movement disorders, and this coincided with significant engagement of DAMP signaling. Using human cell culture systems, we show that factors released from dying neurons signal through RAGE to induce RIPK3-dependent astrocyte activation. These findings highlight a mechanism of neuron-glia crosstalk in which neuronal death perpetuates further neurodegeneration by engaging inflammatory astrocyte activation via RIPK3. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.06.26.546143v1?rss=1 Authors: Bucher, M. L., Dunn, A. R., Bradner, J. M., Egerton, K. S., Burkett, J. P., Johnson, M. A., Miller, G. W. Abstract: Dopaminergic neurons of the substantia nigra exist in a persistent state of vulnerability resulting from high baseline oxidative stress, high energy demand, and broad unmyelinated axonal arborizations. Impairments in the storage of dopamine compound this stress due to cytosolic reactions that transform the vital neurotransmitter into an endogenous neurotoxicant, and this toxicity is thought to contribute to the dopamine neuron degeneration that occurs Parkinson's disease. We have previously identified synaptic vesicle glycoprotein 2C (SV2C) as a modifier of vesicular dopamine function, demonstrating that genetic ablation of SV2C in mice results in decreased dopamine content and evoked dopamine release in the striatum. Here, we adapted a previously published in vitro assay utilizing false fluorescent neurotransmitter 206 (FFN206) to visualize how SV2C regulates vesicular dopamine dynamics and determined that SV2C promotes the uptake and retention of FFN206 within vesicles. In addition, we present data indicating that SV2C enhances the retention of dopamine in the vesicular compartment with radiolabeled dopamine in vesicles isolated from immortalized cells and from mouse brain. Further, we demonstrate that SV2C enhances the ability of vesicles to store the neurotoxicant 1-methyl-4-phenylpyridinium (MPP+) and that genetic ablation of SV2C results in enhanced 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced vulnerability in mice. Together, these findings suggest that SV2C functions to enhance vesicular storage of dopamine and neurotoxicants, and helps maintain the integrity of dopaminergic neurons. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.06.21.545967v1?rss=1 Authors: Boyd, S. L., Kuhn, N. C., Patterson, J. R., Stoll, A. C., Zimmerman, S. A., Kolanowski, M. R., Neubecker, J. J., Luk, K. C., Ramsson, E. S., Sortwell, C. E., Bernstein, A. I. Abstract: Parkinson's disease (PD) is the most common movement disorder and one of the fastest-growing neurological diseases worldwide. This increase outpaces the rate of aging and is most rapid in recently industrialized areas, suggesting the role of environmental factors. Consistent with this, epidemiological studies show an association between exposure to persistent organic pollutants and an increased risk of PD. When combined with post-mortem analysis and mechanistic studies, a role for specific compounds, including the organochlorine pesticide dieldrin, emerges. In mouse models, developmental dieldrin exposure causes male-specific exacerbation of neuronal susceptibility to MPTP and synucleinopathy. Specifically, our novel two-hit model combining developmental dieldrin exposure with the -synuclein (-syn) pre-formed fibril (PFF) model showed a male-specific exacerbation of PFF-induced increases in striatal dopamine (DA) turnover and motor deficits on the challenging beam 6 months post-PFF injection in male offspring developmentally exposed to dieldrin. Here, we hypothesized that alterations in DA handling contribute to the observed changes and assessed vesicular monoamine transporter 2 (VMAT2) function and DA release in this dieldrin/PFF two-hit model. Female C57BL/6 mice were exposed to 0.3 mg/kg dieldrin or vehicle every 3 days, starting at 8 weeks of age by feeding and continuing throughout breeding, gestation, and lactation. Male offspring from independent litters underwent unilateral, intrastriatal injections of -syn PFFs via stereotaxic surgery at 12 weeks of age and DA handling was assessed 4 months post-PFF injection via vesicular 3H-DA uptake assay and fast-scan cyclic voltammetry (FSCV). We observed no dieldrin-associated change in VMAT2 activity, but a dieldrin-induced increase in DA release in striatal slices in PFF-injected animals. These results suggest that developmental dieldrin exposure alters the dopaminergic response to synucleinopathy-triggered toxicity and supports our hypothesis that alterations in DA handling may underly the observed exacerbation of PFF-induced deficits in motor behavior and DA turnover. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.28.538536v1?rss=1 Authors: Tejchman-Skrzyszewska, A., Strzelec, M., Kot, M., Chlebanowska, P., Badyra, B., Sobocinska, M., Zecca, L., Majka, M. Abstract: Parkinson's disease (PD) is a neurodegenerative disease that is an increasing threat to an aging society. The idiopathic form of PD accounts for over 90% of all cases, and the current etiology is still unknown. One of the reasons hindering research on this form of PD is the lack of an appropriate animal models. Among mouse models of the disease, those based on the administration of neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 6-hydroxydopamine (6-OHDA) to the substantia nigra pars compacta (SNpc) or striatum are predominantly used. In these models, there are metabolic disturbances causing oxidative stress in the SNpc or striatum, which ultimately leads to the death of dopaminergic neurons. However, the models used so far have serious limitations, most of all they do not fully reflect the processes occurring in the course of the disease and do not consider the involvement of inflammation in the etiology and pathogenesis of PD. In this study we show that the administration of synthetic neuromelanin, which activates astrocytes and microglia, induces the inflammation and may be involved in degeneration of dopaminergic neurons. Neuromelanin under physiological conditions acts as a neuroprotector, however, released from dying dopaminergic neurons is an important factor activating astrocytes, microglia and causing neuroinflammation. Since one of the causes of Parkinson's appear to be the death of dopaminergic neurons overloaded with neuromelanin and consequent pathological activation of microglia, the use of synthetic neuromelanin reflect the natural pathological processes occurring during the development of the disease. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.05.535706v1?rss=1 Authors: Masilamoni, G. J., Kelly, H., Swain, A., Pare, J.-F., Villalba, R., Smith, Y. Abstract: The globus pallidus pars interna (GPi) is a major source of GABAergic inhibition upon the motor thalamus. GPi neurons are endowed with properties that allow them to fire at a high rate and maintain a tonic inhibitory influence upon thalamocortical neurons. In parkinsonism, the firing rate of GPi neurons is further increased and their firing pattern switches from a tonic to a bursty mode, two pathophysiological changes associated with increased GABAergic pallidothalamic activity. At the thalamic level, GPi terminals display ultrastructural features (large diameter, multiple synapses, large number of mitochondria) that allow them to maintain tonic synaptic inhibition at high firing rate upon thalamocortical neurons in the parvocellular ventral anterior nucleus (VApc) and the centromedian nucleus (CM), the two main GPi-recipient motor thalamic nuclei in nonhuman primates. To determine if changes of GPi neurons activity are associated with neuroplastic reorganization of GPi terminals and their synapses, we used a Single Block Facing/Scanning Electron Microscopy (SBF/SEM), high resolution 3D electron microscopic approach to compare the morphometry of GPi terminals between 2 control and 2 MPTP-treated parkinsonian monkeys. Our findings demonstrate that pallidothalamic terminals in VApc and CM undergo major ultrastructural changes in parkinsonian monkeys: (1) increased terminal volume in both nuclei, (2) increased surface area of synapses in both nuclei, (3) increased number of synapses/GPi terminals in the CM, but not VApc, (4) increased total volume of mitochondria/terminals in both nuclei but not in the number of mitochondria. In contrast, the ultrastructure of putative GABAergic terminals from the reticular thalamic nucleus was not affected in both the VApc and CM of parkinsonian monkeys. Our findings also show striking morphological differences in terminal volume, number/area of synapses and volume/number of mitochondria between GPi terminals in VApc and CM of control monkeys. In conclusion, results of this study demonstrate that GABAergic pallidothalamic terminals are endowed with a high level of structural plasticity that may contribute to the development and maintenance of the abnormal increase in pallidal GABAergic outflow to the thalamus in the parkinsonian state. Furthermore, the evidence for ultrastructural differences between GPi terminals in VApc and CM suggests that morphologically distinct pallidothalamic terminals underlie specific physiological properties of pallidal inputs to VApc and CM in normal and diseased states. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

A new research paper was published in Oncotarget's Volume 13 on December 29, 2022, entitled, “Calcium signaling induced by 15-deoxy-prostamide-J2 promotes cell death by activating PERK, IP3R, and the mitochondrial permeability transition pore.” Melanoma is the deadliest form of skin cancer in the US. Although immunotherapeutic checkpoint inhibitors and small-molecule kinase inhibitors have dramatically increased the survival of patients with melanoma, new or optimized therapeutic approaches are still needed to improve outcomes. 15-deoxy-Δ12,14-prostamide J2 (15d-PMJ2) is an investigational small-molecule that induces ER stress-mediated apoptosis selectively in tumor cells. Additionally, 15d-PMJ2 reduces melanoma growth in vivo. To assess the chemotherapeutic potential of 15d-PMJ2, researchers Daniel A. Ladin, Margaret M. Nelson, Estefani Cota, Catherine Colonna, Colin Burns, Jacques Robidoux, Kelsey H. Fisher-Wellman, and Rukiyah Van Dross-Anderson from East Carolina University and University of North Carolina at Chapel Hill sought to uncover molecular pathways by which 15d-PMJ2 exerts its antitumor activity. B16F10 melanoma and JWF2 squamous cell carcinoma cell lines were cultured in the presence of pharmacological agents that prevent ER or oxidative stress as well as Ca2+ channel blockers to identify mechanisms of 15d-PMJ2 cell death. “Our data demonstrated the ER stress protein, PERK, was required for 15d-PMJ2-induced death.” PERK activation triggered the release of ER-resident Ca2+ through an IP3R sensitive pathway. Increased calcium mobilization led to mitochondrial Ca2+ overload followed by mitochondrial permeability transition pore (mPTP) opening and the deterioration of mitochondrial respiration. Finally, the researchers showed that the electrophilic double bond located within the cyclopentenone ring of 15d-PMJ2 was required for its activity. “The present study identifies PERK/IP3R/mPTP signaling as a mechanism of 15d-PMJ2 antitumor activity.” DOI: https://doi.org/10.18632/oncotarget.28334 Correspondence to: Rukiyah Van Dross-Anderson - vandrossr@ecu.edu Keywords: calcium, mitochondrial respiration, endoplasmic reticulum stress, cancer, prostamide About Oncotarget: Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. To learn more about Oncotarget, visit Oncotarget.com and connect with us on social media: Twitter – https://twitter.com/Oncotarget Facebook – https://www.facebook.com/Oncotarget YouTube – https://www.youtube.com/@OncotargetJournal Instagram – https://www.instagram.com/oncotargetjrnl/ LinkedIn – https://www.linkedin.com/company/oncotarget/ Pinterest – https://www.pinterest.com/oncotarget/ LabTube – https://www.labtube.tv/channel/MTY5OA SoundCloud – https://soundcloud.com/oncotarget For media inquiries, please contact: media@impactjournals.com.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.11.25.517917v1?rss=1 Authors: Villadiego, J., Garcia-Swinburn, R., Garcia-Gonzalez, D., Lebron-Galan, R., Murcia-Belmonte, V., Garcia-Roldan, E., Suarez-Luna, N., Nombela, C., Marchena, M., de Castro, F., Toledo-Aral, J. J. Abstract: The development and survival of dopaminergic neurons are influenced by the fibroblast growth factor (FGF) pathway. Anosmin-1 (A1) is an extracellular matrix protein that acts as a major regulator of this signaling pathway, controlling FGF diffusion, and receptor interaction and shuttling. Furthermore, overexpression of A1 in vivo gives rise to higher number of dopaminergic neurons in the olfactory bulb. Here, using A1 overexpressing mice (A1-mice), we studied the effects of A1 on different populations of catecholaminergic neurons in the central (CNS) and the peripheral nervous systems (PNS). A1 overexpression increases the number of dopaminergic SNpc neurons and alters the striosome/matrix organization of the striatum. Interestingly, these numerical and morphological changes in the nigrostriatal pathway of A1-mice do not confer an altered susceptibility to experimental MPTP-parkinsonism with respect to wild type controls. Moreover, the study of the effects of A1 overexpression was extended to different dopaminergic tissues associated with the PNS, detecting a significant reduction in the number of dopaminergic chemosensitive carotid body glomus cells in A1-mice. Overall, these analyses confirm A1 as a principal regulator of the FGF pathway in the development and survival of dopaminergic neurons in different nuclei of the mammalian nervous system. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.20.512990v1?rss=1 Authors: Kang, S., Choi, L. S., Im, S., Lee, K. W., Kim, D. H., Park, J. H., Park, M.-H., Lee, J., Park, S. K., Kim, K. P., Lee, H. M., Jeon, H. J., Park, H. S., Yoo, S.-K., Kim Pak, Y. Abstract: Parkinsons disease (PD), characterized by degeneration of dopaminergic neurons, share pathogenic features with obesity, including mitochondrial dysfunction and oxidative stress. Paraoxonase 2 (PON2) is an inner mitochondrial membrane protein that is highly expressed in dopaminergic neurons and is involved in the regulation of mitochondrial oxidative stress. However, no drug targeting PON2 has ever been developed for the treatment of PD. Here, we show that vutiglabridin, a clinical phase 2-stage drug for the treatment of obesity, has therapeutic effects in PD models, targeting mitochondrial PON2. Vutiglabridin penetrates into the brain, binds to PON2, and restores 1-methyl-4-phenylpyridinium (MPP+)-induced mitochondrial dysfunction in SH-SY5Y neuroblastoma cells. Knockdown of PON2 by lentiviral shRNA infection abolished the effects of vutiglabridin on mitochondria. In mice, vutiglabridin significantly alleviated motor impairments and damage to dopaminergic neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model, and these effects were also abolished in PON2-knockdown mice, suggesting that vutiglabridin is neuroprotective via PON2. Extensive in vitro and in vivo assessment of potential neurotoxicity showed vutiglabridin to be safe. Overall, these findings provide support for the clinical development of vutiglabridin as a novel PON2 modulator for the treatment of PD. One Sentence SummaryTargeting paraoxonase-2 by a clinical-stage compound vutiglabridin provides neuroprotective effects in preclinical models of Parkinsons disease. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.05.511004v1?rss=1 Authors: Haorei, Y., Vidyadhara, D., Nambisan, A. K., Raju, T. R., Sagar, B. K. C., Alladi, P. A. Abstract: Identification of genetic mutations in Parkinson's disease (PD) promulgates the genetic nature of disease susceptibility. Resilience-associated genes being unknown till date, the normal genetic makeup of an individual may be determinative too. Our earlier studies comparing the substantia nigra (SN) and striatum of C57BL/6J, CD-1 mice and their F1- crossbreds demonstrated neuroprotective role of admixing, against the neurotoxin MPTP. Further, the differences in levels of mitochondrial fission/fusion proteins in the SN of parent strains, imply effect on mitochondrial biogenesis. Our present investigations suggest that the baseline levels of apoptotic factors Bcl-2, Bax and AIF differ across the three strains and, are differentially altered in SN following MPTP-administration. The reduction in complex-I levels exclusively in MPTP-injected C57BL/6J, reiterate mitochondrial involvement in PD pathogenesis. The MPTP induced increase in complex-IV, in the nigra of both parent strains may be compensatory in nature. Ultrastructural evaluation showed fairly preserved mitochondria in the dopaminergic neurons of CD-1 and F1-crossbreds. However, in CD-1, the endoplasmic reticulum demonstrated distinct luminal enlargement, bordering onto ballooning, suggesting proteinopathy as a possible initial trigger. The increase in -synuclein in the pars reticulata of crossbreds suggests a supportive role for this output nucleus in compensating for the lost function of pars compacta. Alternatively, since -synuclein over-expression occurs in different brain regions in PD, the -synuclein increase here may suggest similar pathogenic outcome. Further understanding is required to resolve this biological contraption. Nevertheless, admixing reduces the risk to MPTP by favouring anti-apoptotic consequences. Similar neuroprotection may be envisaged in the admixed populace of Anglo-Indians. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

In this episode, I had the great pleasure of speaking with Mahlon DeLong about the past and future of our field, the most influential model of the basal ganglia circuitry, microexciteable zones in the striatum, the role of the nucleus basalis in Alzheimer's Disease and many other topics. We also touch upon the role of the basal ganglia model for psychiatry, more recent topics such as psychedelics or how instrumental the MPTP model for Parkinson's Disease in nonhuman primates was. Mahlon needs no introduction and can certainly be seen as one of the key founding fathers of modern basal ganglia research and together with Hagai Bergman and Thomas Wichmann directly paved the way to establish deep brain stimulation to the subthalamic nucleus. The episode is enriched by guest questions from Marwan Hariz and Hagai Bergman, as well as planning input from Helen Mayberg. I hope you enjoy the episode with Mahlon as much as I did and thank you for tuning in!

As the powerhouse of the cell, mitochondria are associated with producing energy. However, studies regarding the function of mitochondria suggest that it does way more than powering the cell. In this episode, Dr Elizabeth Yurth discusses the function of the mitochondria in our overall health. For instance, it signals the nucleus to repair the damage done by oxidative stress. Furthermore, the role of mitochondria is also to facilitate improvement in metabolism. Dr Elizabeth also explains how increasing butyrate levels in your gut microbiome is beneficial. This stimulates your mitochondria to release PGC-1α and NPK. As a result, it will have a greater capacity to eliminate waste and harmful substances in the cell. Additionally, we discuss fat tissue, blood sugar levels and metabolism. If you want to know more about the function of mitochondria and how it informs your overall health, this episode is for you. Listening to this podcast will also help you understand your digestive health.   Get Customised Guidance for Your Genetic Make-Up For our epigenetics health program all about optimising your fitness, lifestyle, nutrition and mind performance to your particular genes, go to  https://www.lisatamati.com/page/epigenetics-and-health-coaching/.   Customised Online Coaching for Runners CUSTOMISED RUN COACHING PLANS — How to Run Faster, Be Stronger, Run Longer  Without Burnout & Injuries Have you struggled to fit in training in your busy life? Maybe you don't know where to start, or perhaps you have done a few races but keep having motivation or injury troubles? Do you want to beat last year’s time or finish at the front of the pack? 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If you have a big challenge ahead, are dealing with adversity or are wanting to take your performance to the next level and want to learn how to increase your mental toughness, emotional resilience, foundational health and more, then contact us at support@lisatamati.com.   Order My Books My latest book Relentless chronicles the inspiring journey about how my mother and I defied the odds after an aneurysm left my mum Isobel with massive brain damage at age 74. The medical professionals told me there was absolutely no hope of any quality of life again, but I used every mindset tool, years of research and incredible tenacity to prove them wrong and bring my mother back to full health within 3 years. Get your copy here: https://shop.lisatamati.com/collections/books/products/relentless. For my other two best-selling books Running Hot and Running to Extremes chronicling my ultrarunning adventures and expeditions all around the world, go to https://shop.lisatamati.com/collections/books.   Lisa’s Anti-Ageing and Longevity Supplements  NMN: Nicotinamide Mononucleotide, a NAD+ precursor Feel Healthier and Younger* Researchers have found that Nicotinamide Adenine Dinucleotide or NAD+, a master regulator of metabolism and a molecule essential for the functionality of all human cells, is being dramatically decreased over time. What is NMN? NMN Bio offers a cutting edge Vitamin B3 derivative named NMN (beta Nicotinamide Mononucleotide) that is capable of boosting the levels of NAD+ in muscle tissue and liver. Take charge of your energy levels, focus, metabolism and overall health so you can live a happy, fulfilling life. Founded by scientists, NMN Bio offers supplements that are of highest purity and rigorously tested by an independent, third party lab. Start your cellular rejuvenation journey today. Support Your Healthy Ageing We offer powerful, third party tested, NAD+ boosting supplements so you can start your healthy ageing journey today. Shop now: https://nmnbio.nz/collections/all NMN (beta Nicotinamide Mononucleotide) 250mg | 30 capsules NMN (beta Nicotinamide Mononucleotide) 500mg | 30 capsules 6 Bottles | NMN (beta Nicotinamide Mononucleotide) 250mg | 30 Capsules 6 Bottles | NMN (beta Nicotinamide Mononucleotide) 500mg | 30 Capsules Quality You Can Trust — NMN Our premium range of anti-ageing nutraceuticals (supplements that combine Mother Nature with cutting edge science) combat the effects of ageing, while designed to boost NAD+ levels. Manufactured in an ISO9001 certified facility Boost Your NAD+ Levels — Healthy Ageing: Redefined Cellular Health Energy & Focus Bone Density Skin Elasticity DNA Repair Cardiovascular Health Brain Health  Metabolic Health   My  ‘Fierce’ Sports Jewellery Collection For my gorgeous and inspiring sports jewellery collection ‘Fierce’, go to https://shop.lisatamati.com/collections/lisa-tamati-bespoke-jewellery-collection.   Here are three reasons why you should listen to the full episode: Understand that the function of mitochondria is not only to produce energy but also to enhance cell growth and healing. Learn about the effect of butyrate and antibiotics on the mitochondria, as well as the diet and activities to boost mitochondrial performance. Find out more about the function of the mitochondria in regulating stress, blood glucose and ageing.   Resources Gain exclusive access and bonuses to Pushing the Limit Podcast by becoming a patron! Harness the power of NAD and NMN for anti-ageing and longevity with NMN Bio.   Listen to my other Pushing the Limits Episodes:  #183: Sirtuins and NAD Supplements for Longevity with Dr Elena Seranova #187: How to Slow Down Ageing and Promote Longevity with Dr Elizabeth Yurth #189: Understanding Autophagy and Increasing Your Longevity with Dr Elena Seranova Connect with Dr Elizabet Yurth: Instagram Boulder Longevity Institute — Learn more about research-based longevity medicine developed by Dr Elizabeth Yurth. Sign up at the Human Optimization Academy to access resources on taking control of your health! Mitozen’s Pro ByoMax™ – Probiotic / Butyrate Suppository   Episode Highlights [06:33] What Is the Mitochondria? The mitochondria are bacteria classified as anaerobic organisms. Humans have a symbiotic relationship with the mitochondria. With their help, we can survive outside water and air. Mitochondria also have their own genome. You inherit them from your mother.  The communication between the nucleus and the mitochondria is imperative to our health. [11:00] The Function of Mitochondria In theories of ageing, mitochondria produce free radicals damageing our DNA. The mitochondria release mitochondrial peptides when activated by oxidative stress. These mitochondrial peptides are messages sent to the nucleus to signal it to heal your body. When the mitochondria are stressed, it also activates the unfolded protein response (UPR). The UPR either gets rid of bad protein through autophagy or fixes them. Tune in for more details about how the mitochondria initiate growth and healing. [17:05] Damage in the Cells The body tries to get rid of dysfunctional proteins.  You need to be careful of the amount of antioxidants you take. Taking too much may inhibit your body's response to bad proteins.  You should take your body through a cycle.  You go through an autophagy phase where you clear out the bad cells.    Then, you go through the growth phase, where you induce more toxic stress. In doing so, you can initiate growth and healing.  [19:32] Mitochondria Permeability Transition Pore (MPTP) This pore is a gate that opens and closes the mitochondria. As you grow old or when you are in worse health, it stays open longer. Then, it allows bad stuff to go in and out more often. Melatonin keeps the pores closed most of the time. Spermidine also induces mitochondrial biogenesis by restoring this pore structure. Antibiotics like minocycline may have some very significant benefits to your cell health. [23:14] The Effects of Butyrate on the Gut Microbiome Your microbiome is most affected by butyrate. To consume antibiotics and probiotics, you first have to keep butyrate in your microbiome. Higher levels of butyrate may also help the cell, specifically the mitochondria. It improves aerobic metabolism. High butyrate also regulates your PGC-1α gene to improve your aerobic endurance. Sick people usually replenish butyrate by doing rectal suppositories. To know more about the full effects of butyrate, listen to the full episode. [32:33] Relationship Between the Function of Mitochondria and Gut Microbiome Butyrate increased the PGC-1α and NPK in the mitochondrial level.  As a result, your oxidative capacity is restored, and the mitochondria become healthier. After inducing autophagy and getting rid of the bad stuff, Dr Yurth restricts the food consumption of her patients. Then, she will use spermidine at a higher dose. At this stage, the mitochondrial peptides released will induce the nucleus to have a healthier genome. [36:57] The Effects of Melatonin Melatonin also affects the mitochondrial permeability transition pore (MPTP).  Interleukin-1 beta (IL1β) causes damage to mitochondria. High dose melatonin blocks IL1β. Melatonin also creates a homeostatic reaction in the mitochondria. It’s therefore anti-cancer.  High dose melatonin also restores your circadian rhythm. When you should take it depends on your genes.  20 mg is a high dose of melatonin. This dosage is for people with cancer.  [42:18] The Importance of Mitochondrial Peptides Mitochondrial peptides like the SS-31 helps the endoplasmic reticulum to be healthy.  Exercise helps induce mitochondrial peptides.  MOTS-c as a drug is an alternative for people who can’t exercise.  You can also produce MOTS-c when you exercise.  MOTS-c helps with glucose metabolism, fat loss, turning white fat to brown fat, and overall metabolism. [44:44] Why Brown Adipose Tissue Is Metabolically Active When babies are born, they need something to keep them warm. Brown adipose tissue is functional for heat production and burns calories. White fatty tissues are more common as you get older. It only coats your organs and provides little benefits. Butyrate can convert white fat to brown fat, which can help you boost your metabolism. Fat is also metabolically active. Men who are fatter convert their testosterone into estrogen. Dr Yurth emphasises that a good diet and quality exercise is worthless without looking at hormones. Listen more to learn about how hormones affect your metabolism. [54:20] Regulating Blood Sugar As your blood glucose rises, you will feel temporary stress which is good for you. However, long-term high levels of glucose in your blood are damageing. Dr Yurth mentioned the benefits of continuous glucose monitoring (CGM). Go for a walk after a meal to regulate spikes in your sugar levels. Chromium and cinnamon help maintain blood glucose. However, the positive effects rely on genetics. A recent study revealed that eating protein before carbohydrates shows a lower blood glucose and insulin level. [1:00:36] Enzymes and Breaking Down Proteins Evidence shows that the dysfunction of the metabolic process starts in bile acids. In treating neuromuscular weakness or building muscle, you should focus on your digestive enzymes. Integrate mass proteases and lipases into your meals. Dr Yurth reiterates the importance of keeping your gut microbiome healthy through consuming butyrate.  Good bacteria such as probiotics, which are anaerobes, will not survive the colon site. If you don’t have a healthy gut lining, your immune system will see probiotics as foreign materials. This can cause a histamine response.   7 Powerful Quotes from the Episode ‘I'm gonna make the case that actually every single disease, from cancer, to cardiovascular disease, everything related to ageing, osteoporosis, everything comes down to mitochondrial dysfunction.’ ‘I’m just a big advocate with diet, and with exercise, with everything, everything's done cyclically. Because we want to go through phases all the time where we're getting rid of bad stuff and then regrowing.’ ‘We’re able to use the butyrate for fatty acid oxidation and actually improve aerobic metabolism.’ ’As you're learning, the gut is everything. And now we're learning it may even be imperative to the mitochondria.’ ‘I think what it's going to come down to when we look at this mitochondria, it's not going to be trying to figure out what is my perfect dose of antioxidants. It's gonna be figuring out how do I get that mitochondria with the pores, letting the good stuff in and letting the bad stuff out?’ ‘What it's really trying to get across is just, you know, sensible stuff, we just did a thing you know, about just taking a walk after dinner, right?’ ‘That little bit of stress, like I said, what you know, what doesn't kill you makes you stronger.’   About Dr Elizabeth Yurth Elizabeth Yurth, MD, is the Medical Director and co-founder of the Boulder Longevity Institute. This institute was established in 2006. Dr Yurth is double board-certified in Physical Medicine & Rehabilitation and Anti-Ageing/Regenerative Medicine. She also has a Stanford-affiliated Fellowship in Sports and Spine Medicine. Here, Dr Yurth specialises in Sports, Spine, and Regenerative Medicine. Additionally, she also has a dual-Fellowship in Anti-Aging and Regenerative Medicine (FAARM) and Anti-Aging, Regenerative and Functional Medicine (FAARFM) through the American Academy of Anti-Aging Medicine (A4M). Dr Yurth serves as a faculty member in SSRP (Seeds Scientific Research and Performance) with 25 mastermind physician fellows. Here, she allows herself to stay abreast and teach others in the emerging field of cellular medicine. An active athlete herself, Dr Yurth has worked with numerous sports teams at both the collegiate and professional levels. At present, she works as a consultant for high-level athletes from across the country. She aims to aid them in recovery and optimise performance. Dr Yurth resides in Boulder, Colorado, with her husband and five children. To know more about Dr Yurth’s work, visit Boulder Longevity Institute and connect with her on Instagram.    Enjoyed This Podcast? If you did, be sure to subscribe and share it with your friends! Post a review and share it! If you enjoyed tuning in, then leave us a review. You can also share this with your family and friends so they can learn more about mitochondrial health and include butyrate in their diets. Have any questions? You can contact me through email (support@lisatamati.com) or find me on Facebook, Twitter, Instagram and YouTube. For more episode updates, visit my website. You may also tune in on Apple Podcasts. To pushing the limits, Lisa   Full Transcript Of The Podcast Welcome to Pushing The Limits, the show that helps you reach your full potential with your host, Lisa Tamati, brought to you by lisatamati.com.  Lisa Tamati: Lisa Tamati your host here at Pushing The Limits. Super excited that you're here with me again today. Thanks for tuning in. I do love and appreciate your loyalty. And I would love to hear from you. If you've got something to say about the podcast, you’ve got some comments and questions about some of the topics that we have raised, please do reach out to us. We love hearing from our listeners. And if you can give us a rating and review if you're enjoying the content, that really really helps the show.  We've also got our Patron VIP premium membership now open. If you love our show, if you love what we do, what we stand for our values, our principles, the work that we put into this podcast, which we've been doing now for five and a half years, without any money or any—just for the love of it and for the passion of it. If you want to help support us and keep us going and want to get a whole lot of premium membership benefits, then head over to patron.lisatamati.com. I would love you to join our VIP tribe. That's patron.lisatamati.com. For the price of about a coffee a day or a little bit more, you can be involved. There's two tiers in there, with different levels of premium member benefits. And we would love you to join us there. So if you can please do.  Now today's superstar is Dr Elizabeth Yurth. And if you follow the podcast, you might have remember that name because she was on just a few weeks ago. And she is now one of my favorite teachers. I have been learning from her at the Bone Longevity Institute of Human Optimization Academy. And she is a brilliant teacher, and a brilliant orthopaedic surgeon and longevity expert. And she offers the world's most advanced research-based health care. And it's all customised to you. And the information that we're going to share with you today—today's topic if you like, is all around mitochondrial health. Now we do deviate a little bit because as we do in these conversations, we go off on a few tangents. But it is really all about understanding what your mitochondria are, why you need to know about it, how to keep them healthy, because these little bacteria if you like, and these little powerhouses of our cells are absolutely crucial to health and longevity.  And Dr Yurth says that the mitochondria, she thinks, are at the very basis of all diseases. So when these little guys go awry, that's when diseases come into play. And everything from cancer, chronic fatigue, to all of the diseases right across the spectrum can be affected by mitochondrial health. So we do a bit of a deep dive into that today. So I hope you enjoy this session with Dr Elizabeth Yurth. She's a lady who walks the talk. She's an incredibly amazing person, athlete, orthopaedic surgeon. She loves this. She breathes it the way she loves, as you know, in complete alignment with what she also teaches, so make sure you check out all her links in the show notes. Right.  Now before we go over to the show. Just want to also let you know about our NMN, our supplements. They’re longevity and anti-ageing supplement. We are into longevity. We are into health span. We are into increasing our lifespan and healthspan. So if you want to get into having—to boosting your NAD levels in your body, we've recently done a couple of episodes with Dr Elena Seranova on this topic, then head over to nmnbio.nz. And grab your NMN supplements over there to get your longevity regime underway.  And in today's podcast, we talk a little bit about this. We talk also about spermidine, which we've also mentioned in other podcasts. There are some amazing compounds out there that are going to help us stay healthier and longer. And there's a lot of techniques and things that we can actually engage in. We don't have to be passive bystanders to our ageing, we can do things about it, we can slow it down, and even reverse it in some places. So I hope you enjoy this episode. So do check out my Longevity Supplement over at nmnbio.nz. And enjoy today's show with Dr Elizabeth Yurth.  Lisa: Well, hi everyone and welcome back to Pushing The Limits. Super excited to have another wonderful guest that we've actually had on before and back by popular demand. That was a very, very popular episode. So I have Dr Elizabeth Yurth with me. Hi, Dr Yurth, how are you doing? Dr Elizabeth Yurth: Lisa, thank you for having me again. I love being with you.  Lisa: Oh, it's just that, our last episode was just so full of information that I've had it on repeat going, for me, because there's so much in there and so many people have written and have been asking questions. So I want to get started by saying if after this interview, you want to talk to Dr Yurth and one of her team at the Border Longevity Institute, you can do that even when you're in New Zealand or Australia, you can do teleconsults. And yeah, so if you are facing some difficult health problem, and you really want some help, make sure you do that. And we'll have all the links in the show notes and so on. And before we get underway, there is a Bold Longevity of—what is it called, optimisation?  Dr Yurth: Human Optimization Academy, right? Yeah, from the Border Longevity site, or just go to bliacademy.com and sign up. But you guys have definitely signed up for that we actually are trying to really put together tons—and all the information you guys need to try. And you'll have one place where you can go get all of these things that we talked about, and all the things that Lisa talks about, and really be able to learn about them. Because as we know, doctors don't really learn this stuff very well. So you guys have to do it yourself. And so we're trying to give you a place to do. It's coming from a very experienced... Lisa: Yeah, and if you want on the latest, so make sure bli.academy.com. And I'll put that in the show notes too guys, so you can find it.  Now today's subject is mitochondria, one of Dr Yurth’s favorite subjects. Okay, for starters, what is a mitochondria? Dr Yurth: What's really so cool about mitochondria, right, is they're actually they were actually their own little bacteria. So they invaded us back when we were threatened to kind of moving from an anaerobic to an aerobic environment. So when we went from sort of anaerobic organisms to actually living in air, we couldn't do it. And so these little bacteria got into the cells, and they formed a symbiotic relationship, so that we could survive outside of water and air. And so they were responsible for us being able to move out of the ocean and into an air or an aerobic environment. Well, they're actually their own little organism. Right? I mean, that that is weird, right? That we have this essential part of our cell. Now our essential part of survival is actually its own organism.  And it was a one celled organism, it gone to formed a symbiotic relationship, it allowed the bacteria to survive living inside ourselves. And if we allowed ourselves to survive, so amazing. And that's why they're so unique is that they actually contain a whole genome that is separate from your nuclear genome, right? So they have a mitochondrial genome that's completely different. And it's only inherited from your mother. So that mitochondrial genome is not inherited from your father at all. It's probably one of the reasons your mother's health at the time, because even though the mitochondria has its own genome, that genome is impacted by things you do. So if I have a baby, and I'm super unhealthy, I've altered that mitochondrial genome. And then I've transferred that mitochondrial genome only from me—the dad was great and doing everything right—to my children. So that's one of the... Lisa: So that’s the epigenetic…. Because I'm just about to go through IVF, as I said before, very interesting for me. So even though I'm going to have an egg donor... Dr Yurth: You wanna make sure she’s healthy, right?  Lisa: Yeah, she's just—she is, and we've got her on everything. Her DNA is coming into the egg, but actually, my mitochondria will be a part of this baby, if we have one. Dr Yurth: So you will alter—so basically, she's, you're going to be, the baby will have her mitochondrial DNA. But because you will be growing this baby, you will be altering that mitochondrial DNA by epigenetic influences that you're doing, right. So now you're going to be changing some of that DNA structure, or the genome of that mitochondria by things you're doing. The mitochondria, so even though it's coming in, and again, you want her to come in with this great mitochondrial DNA in the first place. Right? So we want this good genome in the first place, which is why you do want her to be healthy and fit and all those things. And younger. But then you know all about the epigenetics, and so you're going to be potentially altering some of that, too. So that's one of the really amazing things. Now, what we used to think is, all the mitochondria did was do oxidative phosphorylation, and make energy, make ATP. And that's what they did. They were our energy powerhouse. That's all we ever learned, right? High school was like, ‘Oh, the powerhouse of the cell’.  So we now know, they do a whole lot more than that. So they're not just responsible for aerobic metabolism, and making ATP. So they're not just energy production. And in fact, there's the communication back and forth between the nucleus of ourselves and these mitochondrial DNA that's imperative to health. Well, I'm gonna make the case that actually every single disease, from cancer, to cardiovascular disease, everything related to ageing, osteoporosis, everything comes down to mitochondrial dysfunction. Lisa: Wow. So this is pretty– Dr Yurth: It's imperative and, and you're gonna start reading more about this, is that the key to fixing our health is going to be fixing the mitochondria. And we've already figured out like, you know, you I know you're big into NAD that, improving NAD and I know you have a product that does that. And that is— that's critical, right? To mitochondrial health. We know that's critical to mitochondrial health. But there's more to that story. And the big thing is that is that piece of communication, that mitochondria sends messages out to the nucleus, and the nucleus sends messages back to the mitochondria. Lisa: Okay, so what are these messages that they’re sending backwards and forwards? And why does this have to do with the function of the mitochondria itself? Dr Yurth: Well, there's, as the body goes through the oxidative phosphorylation pathway, that Krebs cycle, that cycle that makes energy, right. And we know that we create these free radicals. And that's been one of the big theories of ageing is this free radical theory of ageing, that mitochondria produce all these free radicals, as free radicals overwhelm the body, they damage cells, and we get damaged tore into our DNA? Hmm. Lisa: So we all thought that antioxidants would be the answer, recommended… Dr Yurth: Right. We just take a bunch of antioxidants into the mix, and you're going to be great, because now, all those free radicals, you're not going to have any damage. The problem is that we know that there's been this—the mitochondria has a very, has a way to handle this oxidative stress. So there's a few things that happen. Obviously, stress is really critical to the mitochondria’s health. So as it creates these free radicals, and and it's rust by things, it actually produces what are called mitochondrial peptides. So it has its own genome, right, that's now been activated by this stress. And it creates these—its own peptides that no other structure in your body can produce. So it's producing these little chains of amino acids.  And there's quite a few being developed now or that or that we were learning about, but the sort of the three main ones that we kind of have a pretty good knowledge about right now are something called MOTS-c. There's another one called humanin, and another one called SS-31. And those are what—the SS-31s, and a group of them are called small humanin-like peptides or SHLPs. Those peptides, so once the mitochondria is stressed, it encodes this DNA to say, ‘Oh, you need to go out there and tell the nucleus to do some good stuff’.  So these mitochondrial peptides now go outside of the mitochondria, and they tell the nucleus to to heal things and get stronger and do better. And then that sends messages back to the mitochondria. So that stress, that oxidative stress actually, it's just like, you know, what doesn't kill you makes you stronger. Lisa: And actually it’s a fact on this. Dr Yurth: It’s really a fact that mitochondria health, that these medical peptides are imperative to health. In fact, humanin which were first developed actually was looking like a cure for Alzheimer's. And it may be really—well, it may be actually very, very baffling here, but very, very helpful in dementias and a lot of other diseases. We know that higher levels of humanin, people who live to be a hundred and above have much higher levels of humanin, so we know that these mitochondrial peptides, the higher they are, the healthier you are. No mitochondrial stress. If I just impound my body with antioxidants all the time, then I'm actually probably doing some damage. So cancer, right, so where—now again there, I can also overwhelm, right?  There's also another response, the mitochondria have, it's called the UPR, unfolded protein response. So as the mitochondria are stressed, and these damaged proteins that are produced when we're under stress, right, we get damaged or proteins, that's where we're kind of linking that to Parkinson's and Alzheimer's and some of the plaques that form... Lisa: The tau proteins and things.  Dr Yurth: Yeah, yep. When the mitochondria is stressed, it actually sends messages out to the nucleus to activate what's called the UPR, the unfolded protein response. A little protein response actually takes these bad proteins and it strings them back out and makes them normal. Or it says, ‘These guys are so damaged. Let's just get rid of that mitochondria and initiate basically autophagy or mitophagy, eliminates the bad mitochondria that are too damaged. There's too many damaged proteins. We've overwhelmed the unfolded protein response’. Now it initiates this response to kill off the bad mitochondria.  See, if I'm just now taking a ton of antioxidants. Maybe I've blocked this response to get rid of all these bad proteins. Right. And I'm actually inducing more of these bad, abnormal proteins that are going to cause damage.  Lisa: I've talked on a couple of episodes with Dr Elena Seranova about—who is a molecular biologist on autophagy. And I think we talked about it too last time. So that's getting rid of the damaged proteins in the cells or in the mitochondria itself, getting rid of it. And we talked about fasting last time and how critical fasting is for autophagy in getting rid of these bad proteins and clearing things out.  So if we—so you're saying we can overwhelm this protein, and what do you call unfolding...  Dr Yurth: Unfolded protein response, UPR.  Lisa: Yeah, we can overwhelm it with too many antioxidants and actually stop it... Dr Yurth: Stop the UPR from being activated. So now we don't actually kill it, we don't actually—either fix the damaged protein or get rid of the cells that are too damaged. Lisa: Wow, okay. And so in this is this two-way communication between the mitochondria and the DNA, this is the nucleus of the cell. This is all within the—if we picture a big, nice fat round cell, and inside, you've got thousands of mitochondria per cell. And you've got the actual nucleus, which has that nice double helix, you see in the graph–  Dr Yurth: Where all the DNA is. Lisa: –where the DNA, your code for life is–  Dr Yurth: Right.  Lisa: And these are talking backwards and forwards to each other to keep the health of the cell good. And then when we do autophagy, or mitophagy, we're getting rid of the damaged parts of the proteins that have been damaged through—is this through, so the damage that occurs in the cells is happening because of DNA breaks? And what are toxins and things like that, right?  Dr Yurth: Exactly, these reactive oxygen species that you know, they're starting to damage the DNA too much inside the mitochondria and creating abnormal proteins. Right? So now we've created these dysfunctional proteins that are going to do damage, so the body tries to get rid of them. And it's not, I'm not gonna say there's no place for antioxidants, right? But what you have to be careful of, is sort of cycling through phases where you're off of your antioxidants, and maybe inducing more autophagy, right. So we now want a little more oxidative stress to induce this healing response to give the cell some stress, and then maybe going on antioxidants for a little while to make sure that we don't ever have too many. Lisa: Yeah, if you've gotten a lot of antioxidants, or sorry, or oxidative stress, because maybe you're exercising a heck of a lot or you've had an infection, or you've got something other high stress...  Dr Yurth: You eat like crap, or you're fat or… Then you might need extra antioxidants. And just to support the baseline of your functional health. But even those people, right, need them off and on, they should not be constantly. They should do phases, right? They should cycle it. I'm just a big advocate with diet, with exercise with everything, everything's done so quickly. Because we want to go through phases all the time, where we're getting rid of bad stuff, and then regrowing and getting rid of bad stuff and regrowing. Right? It’s just like cleaning your house. You got to get rid of all the crap, but then you're gonna… Lisa: Bring the new groceries. Dr Yurth: Yeah, right. It's get cluttered again. And then you got to go clean it all out again, and things get cluttered again. Yeah, I mean, that's the world's clutter wouldn't happen, but it does, right. Even the most pristine non hoarder person, there's still clutter that happens, and you still have to do your spring clean outs. And that's—so I like to think about the body in the same way, you know, going into the spring clean outs where you go through a big autophagy phase where you're fasting, we're using hydro spermidine, where you're using things that will help to really clear out all the bad cells, all these damage, mitochondria that are producing too many reactive oxygen species, right? And then going through growth phases, where where I'm now maybe I'm inducing a little bit more toxic stress, I'm exercising harder, I'm lifting more weights, I'm running more, right, I'm inducing more oxidative stress. Maybe I'm eating more calories during that time. Now there's more oxidative stress cells a little bit stressed that actually initiate some growth and some healing. Right. And then I can do the same thing over and over again. But there's really interesting new research leads when you kind of look at ‘Okay, well, how does this all make sense’? So it's probably going to come down more to this. This is what's called the MPTP or mitochondrial permeability transition pore. And what they've now found is that that's probably where we need to focus is this little pore is letting stuff in back and forth through the mitochondria. So the right amount of things get through. So we know this little pore opens and closes. As we're in worse health, or older, it stays open longer, allowing more bad things to go In and out. So it's designed to open periodically, closed periodically. So for brief periods.  So what a lot of focus now is on anti-ageing. And mitochondrial health is focusing a little bit on this mitochondrial transition pore. In fact, there's a really cool study just came out where they're actually taking out these mitochondria and actually changing the pore structure for treating cancer. So they can actually make the pores in these cancer cells more permeable, so they can get drugs with a little nanobot that's poking holes in the mitochondria.  But on our home base, is what we really would rather do is keep these little mitochondrial transition pores closed most of the time, let them open periodically. So there's some interesting things that do that, melatonin does that? Oh, so higher dose melatonin seems to work primarily on this pore to actually regulate keeping it closed more often. So it’s spermidine, that's one way spermidine induces cellular or mitochondrial biogenesis is by restoring this pore structure. Lisa: And we're big into augmenting spermidine. I've just got my first shipment, I'm working on getting that down here guys.  Dr Yurth: Spermidine is kind of amazing. Because it really is so good for mitophagy, getting rid of bad mitochondria, but also mitochondrial biogenesis probably because it does focus a little bit more on this pore. Making more mitochondria, right. Right, make more mitochondria, we need more mitochondria.  The other thing interesting, I don't know how many of—how you or your listeners have looked at things like minocycline, right? Antibiotic, we always think antibiotics are bad, right? Yeah. Well, interestingly, minocycline and doxycycline. And minocycline is a little bit better, probably actually has a very nice anti-ageing effect, used periodically, to actually close off these pores, and let the cell kind of develop and grow more than mitochondria grow more. So minocycline has a really distinct effect on the mitochondrial transition pore as well, for this permeability pore. So there are a few simple things that you can use, and I like.  Lisa: And it doesn't want your good microbes and stuff when you take them. Dr Yurth: You know, definitely antibiotics have the downside of changing the gut microbiome. And we know that there's downsides to that, which is why you're not going to stem minocycline all the time. But like anything, it appears to have some very significant benefits in our cell health. So by doing that, maybe twice a year, doing like a 10-day course of minocycline, you can actually restore cell health. Now, after that, do you have to really work on gut health? Probably depends on how bad your gut is. So if my gut is super healthy, it's probably gonna regenerate, divide, right? Otherwise, it would, I have a lot and I know you're really interested in some gut microbiome stuff. Because you're gonna be a really—you're gonna see a really big connection coming up here soon between the gut microbiome and mitochondria even. But we know the gut microbiome is most affected by butyrate.  So using tributyrate, which is sort of pre-butyrate that can turn to be right in your intestine. So if I had somebody on an antibiotic, do I throw—I'm just gonna throw probiotics into the mix? Well, no, because the probiotics aren't gonna survive. So what you have to do is first throw butyrate into the mix. Remember what the good bacteria in our gut do that we eat fiber? The anaerobic bacteria. Turn that fiber into butyrate. Butyrate has all these far reaching effects. Number one, it's imperative for the colonocytes, the colon cells to be healthy, that's what they—that's what they use for energy is butyrate. So they're different from your other cells, they use butyrate for energy. So when they use butyrate, for energy, I have these nice healthy colonocytes, they create a nice anaerobic environment where my anaerobes can thrive. And they can make more butyrate. And you have this nice cycle. But butyrate has some really interesting effects. There was a great study for your distance runners using butyrate to increase performance. Because higher levels of gut butyrate also seemed to help the cell, the mitochondria, and actually produce you actually, were able to use the butyrate for fatty acid oxidation and actually improve aerobic metabolism by having higher levels of butyrate.  Lisa: Was it like yeah, the athletes with keto. Yeah, because butyrate is like, isn't butter got butyrate in it? Or am I? Butyrate, butter.  Dr Yurth: Oh, butter. So butter does have butyrate in it, yes. So you can even increase butyrate by eating a whole lot of butter. You'd be—so your medium chain triglycerides, the short chain fatty acids do have butyric acid in them. The problem with when you eat butyric acid, when you eat butyrate, it doesn't really reach this lower intestine very well. Okay, and so even though it has some benefits, probably some other places, you really have to get the gut bacteria. And so the only way to really get butyrate to the lower intestine is either to take a pre-butyrate form, which is I like tributyrin, one has research behind it, or to use it rectally. So that's the other thing you can do is use it rectally.  Lisa: Okay, then that gets direct into the colon and then can get the right to the cells there.  Dr Yurth: Yeah, and this actually has a genetic—do you remember your PGC alpha gene? So when you get hired to get butyrate, you actually upregulate PGC alpha. And that's one of the things that improves aerobic endurance in your long distance athletes. You can actually—they did a study with butyrate on improving endurance in sort of your distance runners, your higher level endurance athletes, and besides, it's significant improvements. Also in race horses. Same thing.  So butyrate does affect mitochondria in other places, including skeletal muscle, and around that. So there is this big connection that we're just learning about between the gut microbiome and mitochondria. So if I'm going to put somebody into minocycline. I'm going to also make sure I have them on tributyrate so I'm keeping that nice anaerobic metabolism going. I'm making sure I'm getting butyrate to myself. Now I've repaired the mitochondria. I've given it another source to work better. And I'm going to have overall better endurance, better health, better aerobic metabolism. Better Vo2max. Lisa: Yeah, wow, that's just crazy. So butyrate—but if we just taking butyric acid or in through butter or that type of thing. Brother just arrived in the background. It’s all good. Podcast life. At least the cat’s not running from down as well.  So butyric acid, when I take it in the form of say medium chain triglycerides or butter and stuff, it's not going to help my colonocytes and my colon, but I still get through to the mitochondria and help. Dr Yurth: Yeah. I mean, there's significant benefits to it, but you really want to replenish the butyrate in the lower intestine, where you really need that for overall health. You really have to either do it rectally, or take it as a pro butyrate or a pre-butyrate form or tributyrin– Lisa: Tributyrin. I'll put that in the links.  Dr Yurth: You know what is interesting, my patients who have the worst, now are the sickest, like I take care tributyrate. I have no problems with it. I'm fine. I feel good and most people. But if you're sick or not well or have a bad gut and you take it, you'll feel pretty miserable. Because you actually can't turn it into butyrate very well and it actually causes a lot of GI distress. So some of those really sick people the only way to replenish butyrate first is to do a rectal suppository. So you can get rectal suppositories of butyrate right. You do like a high dose, like two grams of a rectal suppository, butyrate, replenish the butyrate then you throw like a spore probiotic or probiotic and now I've created this nice anaerobic environment I've replaced the good bacteria. Now actually they do fine as a maintenance with the tributyrate now that I've restored the gut health. For people who are not well, and I'll tell you, if any of you patients or your people, you talk to your clients, you talk to them use him take tributyrin, and they get they're like, ‘Oh, I'm nauseous, I can't take it’, or ‘Gives me diarrhea’, but it's because they have a bad gut and you've got to work, you know, right? Yeah. So tells you, right, that you need to replenish the butyrate. And again, the only way to do is rectally. Lisa: Can you buy that as a consumer without a doctor who's until…. Dr Yurth: But there is a company and I don't know that, here in the US that's called MitoZen. That does make a pro-butyrate, it's a suppository. It's a two-week course, you have a high dose butyrate and it's actually pretty cool as a spore biotic mixed in. So I use that product a lot. It's on the pricey side like all this stuff. But I really find like a two week course of it. People do pretty well. All you do is two weeks of it, and then you can get them into the oral much less expensive form. The rectal butyrate smells bad. One of my patients, like ‘All my dogs are following me everywhere’. Other people—when you're doing I don't think other people can smell it on you but you can kinda smell it when you do it. It’s kind of like urine. Some people don't like the smell of, I don't mind the smell of that, but some people say they don't like the smell of that either. Lisa: Okay, men and tributyrate, so if he’s not really sick, so if they’re really sick. So if you've got something like Crohn's disease, or IBS, or something– Dr Yurth: Those people you wanna do the rectal, and they do amazing. I will tell you, they do amazing. There's a big stage just coming out with Crohn's being a mitochondrial disorder, too. It's got mitochondrial disorder, but IBS, your SIBO patients, you put them on the rectal butyrate, two weeks so that they do absolutely amazing. Honestly, it's incredible how well they do in a lot of illnesses. I mean, it's been our go to for a whole lot of different disorders. And it's amazing how well it works. As you're learning the gut is everything. And now we're learning it may even be imperative to the mitochondria. Lisa: So how does it connect with mitochondria? So that piece here I've sort of like, haven't quite got in my head. How does—like you said, mitochondria are the basis of health, because they are the ones that are producing the energy for the cell, talking to the nucleus, they're causing this cascade of different events in the cell. They're actually producing ATP, which is our energy. So if you look at things like say, as you get older, your EGFR goes down, your function of your kidneys, in other words, starts to deteriorate. And this is, as an ultra endurance athlete, we smash the crap out of my kidneys with rhabdomyolysis a hundred times. I've had real battles getting my EGFR back up and managed it to quite a good degree, but it's still a problem. And as we get older, we sort of lose about 1% a year they say, of kidney function.  So then it’s just another example of it's actually the mitochondria that in this case, and the kidney cells that are not able to do their energy production to do what the kidney cells should be doing. So how can we reverse that train and get our kidneys working in this case, or our brain or in another case, or heart cells? All of these areas are affected by the mitochondrial function. And how does that link connect to the gut situation? Dr Yurth: So it connects to the butyrate because what butyrate does, at the mitochondrial level, is increases PGC-1 alpha and AMPK. And so you're, you're inducing on a genetic basis, a better oxidative capacity, right? So you're restoring the oxidative capacity to the cell, the mitochondria healthier. And so it's really working—the butyrate and searching fatty acids are really working on a genetic level, probably primarily at PGC-1alpha, I think we'll probably find more and more because this is very new. But it looks like that PGC-1 alpha is where it's happening is a very distinct effect on mitochondria. And then the AMPK through the ACC pathway.  So basically, I think, if you think about it, probably from your training and everything, think about it as an epigenetic influence changing genetic output, right. So that's probably where the short term fatty acids are working in terms of mitochondrial health, I think there's going to be more to that story. You're right, kidney disease brain to these, everything comes down to we have to have mitochondrial health. So exactly what you said, first, have a healthy gut, let's replace the butyrate. Because we know that that's important for those pathways, then, what we have to do is go through phases where we really induce mitophagy. That's where you're fasting and your spermidine comes in, right. So we've got to basically induce, get rid of all the bad mitochondria. So that's gonna induce mitophagy right. So get rid of all the bad stuff.  And then we want to do more of a build up phase. So what I'll do is all patients go through different courses, 6-12 weeks of really kind of more real time food restrictions, and using spermidine at a higher dose, and I'll get them sort of clean slate right. Now I want to regrow and that's where I want to actually regrow in. So I'm gonna have them now, get a little bit less out of eat a little bit more a little less calorie deficit, I want to create a little bit of oxidative stress because now I'm going to induce those humanin-like peptides, those mitochondrial peptides, my MOTS-c, SS-31, the small humanin-like peptides, humanin itself. So we know that those are so imperative for ageing, and that when those peptides are released, they induce your nucleus to have a healthier genome. So now I'm going to have everything else be healthier, because it's going to send messages back to the mitochondria, mitochondria is going to be healthy, but then that's gonna get overwhelmed after a while. So then we go back into our, you know.  So when you think of things that way, always that sort of breakdown-cleanup, breakdown-cleanup, kind of an easier way to live right? Don't get bored. Always live in this super restricted capacity. Lisa: Especially with calorie restriction and things. Dr Yurth: Yeah, like caloric restriction and right eating very low calories. Yeah.  Lisa: It makes you miserable too.  Dr Yurth: That’s right. And so when you can tell—when you tell people listen, I want you to do this for 12 weeks, and then we're gonna let you kind of, you know, have a little me, I'm not gonna tell them go eat cake, but we're gonna be able to, you know, do a little bit more and go through growth phases. And people feel better, and they look better and they have more muscle mass, if you're always in that AMPK state right, that break down, but not really break down state but that more longevity stat, more catabolic state more, yeah. Which is good for longevity, right? But when you look at those people, they always look so healthy. I'll look at someone's people. And you're like, I mean, sometimes they don't have much muscle mass, their hair is thinner. So we do want to go through these phases where we allow the body to kind of grow a little bit, right, especially if you want some muscle, we know that muscle is imperative to health.  And thenI think we're sort of in the long term now they've got the mitochondria in this good homeostatic balance state where I've gotten it, but how do I keep that reactive oxygen species as low as possible? That's going to be where you look at them. That mitochondrial transitional pore, where, how do I keep that balance? And I think that's where maybe a lower dose spermidine every day, like one or two tablets every day of spermidine but I love melatonin for that purpose.  Lisa: I wanted to come back to melatonin. So I understood like melatonin—I was a little bit hesitant to take melatonin because it can change or can fix your circadian rhythms and so on. But after listening to you a couple of times talking about melatonin, why is it not a problem then? Do we take it at nighttime? And what sort of dosages do we need to take?  Dr Yurth: It’s interesting. I mean, we will dose—so for my osteoarthritis patients who have, for instance, high levels, most patients who have diffuse arthritis, or degenerative discs have very high levels of a cytokine called interleukin 1 beta. Interleukin 1 beta is very damaging in mitochondria, that's probably one of the reasons you get cell death and, and your chondrocytes all die off. So one of the things we know blocks interleukin 1 beta is higher dose melatonin. We also know that that's very anti-cancer, right? Probably for the same reason it's creating this balance, this homeostatic reaction in the mitochondria. So I actually like, in those patients, high dose melatonin, a high dose melatonin sounds interesting. Unlike the lower dose melatonin, it sometimes actually has more of a stimulating effect. But it actually does help restore your own circadian balance at a higher dose.  I have a lot of people who take it in the morning, because if they take it at night, they actually are stimulated by it. If you take in the morning, they're sleepy at bedtime, and they sleep through the night. While I'm working with your own. Your super charismatic nucleus and tinea, we're kind of brain level, a kind of balance you back out. Lisa: So what sort of level is like, I'm at the moment, just me personally, anecdotally, I'm taking a five milligram dose of melatonin at night time to optimise my sleep. And is that a low dose? Is that or is that a high? Yeah, what is the high dose? Dr Yurth: So high dose is like 20 milligrams. We use the high doses in our people who have osteoarthritis primarily, cancer, we use high dose melatonin, especially your breast cancer patients will use high dose melatonin. So we'll use that, you know, as a trigger adjunct. Not always, you really have to kind of work with people, there's people who do great take in at night. One of my sons does great, it's 20 milligrams of melatonin at night. Sleeps through the night and wake up early in the morning. Me, I actually take it in the morning. If I take it at night, I'm wide awake all night. But if I take in the morning, I have a really nice, good sleep with good deep sleep on my Oura ring. I get a good  hour and a half of deep sleep. So it seems very different in different people and how it's interacted. And I'm sure that has to do a lot with kind of genetic, what are your clock genes? So I think that that probably has a little bit of a genetic influence. And I do have people who just don't follow—can only tolerate very low dose. You know, but we're finding more and more reasons to be very cautious with oh, you don't really want to take more than three to five milligrams of melatonin. Yeah, really finding that the higher doses seem to have a very advantageous effect on... Lisa: Without putting your body clock out. You're super right. Dr Yurth: Actually, potentially really benefiting your body clock, your circadian rhythm, which is critically important. And right now, that's one of the sort of easy things we can do that we know is going to be working. And as I said, I think what—it's going to come down to when we look at this mitochondria, it's not going to be trying to figure out what is my perfect dose of antioxidants. It's gonna be figuring out how do I get that mitochondria with the pores, letting the good stuff in, letting the bad stuff out?  Yeah, in the right sequence because we know that, for instance, cancer cells that port stays open all the time. There's this very imbalance in this other mitochondria are really getting all this stuff all the time. So we know that a huge factor to health is trying to restore this normal port. I think that we're—there's a drug that's coming out. I can't remember the name of it. Yeah, I can't remember the name of it, but that will probably be actually really, if we can get it will be actually really interesting. It's actually coming out for the treatment of ALS. But that looks like it might be really helpful for that pore.  Lisa: They’re shutting the mitochondrial pore.  Dr Yurth: Yeah, I mean, if that will be something we can get. I don't know. But we'll find more things. Like I said, I think minocycline is a really nice thing to go to, like twice a year, I'll use a 10-day minocycline course, really benign.  Lisa: Minocycline. How do you spell it? Dr Yurth: So, minocycline, M-I-N-O-C-Y-C-L-I-N-E. Cheap antibiotics. I mean, it's like a $10 antibiotic. Right. And that has, but it has really—and it's been looked at in the anti-ageing field for a while, but we kind of weren't so clear of its effect on the mitochondria. Well, now we actually have found it's actually working on this pore, to actually balance out and keep the pore closed more, which is what you really want. When we're young, the pore is not open as much as it does when we’re old, there's less bad stuff coming through the mitochondria. Lisa: So itis getting porous, isn't it? So basically, the membrane is getting porous.  Dr Yurth: Exactly, that's probably where—like some of the mitochondria peptides like SS-31, which was the cardia lipid membrane, which helps them that endoplasmic reticulum inside the mitochondria to be healthy. So that's why peptides like that are so beneficial. Lisa: Yeah, yeah. And there's lots of, you know, we can't get these fancy peptides, unfortunately, that easily. The caveolae pan is an enzyme that is a very important enzyme for us. It's a stabilising enzyme, isn't it? So, we want more of this and this is what one of these peptides is right. And so hopefully, there's going to be more research around that and more drugs even coming out around that. Dr Yurth: Yeah, and remember that one of the ways we induce some of these mitochondrial peptides is exercise. Right? MOTS-c is a little bit of stress for our body, right and so it reduces the mitochondria to produce some of these mitochondrial peptides. MOTS-c which is kind of considered exercise in a bottle because you can actually give at least mice you can give them MOTS-c— basically this mitochondrial peptide and it acts just like exercise. Lisa: Exercise hermetic. Dr Yurth: Yeah. So it's very cool. Of course, it's very expensive and... But way cheaper to go exercise, but it's a nice thing to offer people who can't exercise for some reason. Like, you'll have an injury or elderly people who are just so sarcopenic and trying to get them to do anything until you build a little bit of muscle is almost impossible. So things like that are going to be really nice in that realm as peptides like MOTS-c.  There's a whole company here that is actually just working on these mitochondrial peptides as drugs for treating things like this. Right now, we know that one of the best ways to produce MOTS-c is to exercise, stimulates your mitochondria to be a little stressed. Mitochondria produces more MOTS-c. MOTS-c helps with glucose metabolism, it helps with fat loss, it helps with turning white fat into brown fat helps. It helps with kind of overall aero metabolism. Lisa: Just briefly on that. What is white fat versus brown adipose tissue, you know, brown fat? And why is brown metabolically active?  Dr Yurth: Yeah, so you know, white fats what—that fat we get as we get older and you know, it's really doing nothing beneficial. Brown fat is what little kids have, right? Brown fats—we look at babies or you look at little kids and they have that little chubbiness. Well, that's usually brown fat. Why? You know, maybe boys made fun because I'm always cold and so I'm way overdressed. My kids, but little kids don't get nearly as cool. We don't have to like them quite so bundled up as we do, because they're really covered with brown fat, which is metabolically active, that's what it was designed for. And when you're born you have this brown fat, you can stay warm. I mean, really, we were meant for survival, right? These babies who are born, they need something to keep them you know. Also there when you were caveman and you were just laying there in the cave, you survived.  So brown fat is metabolically active, it's helping for warmth and heat production. It's actually burning calories. White fat is what we get as we get older and we just eat too much and we sit around too much. And all it does is coat our organs and do nothing beneficial. So brown fat actually you can convert white adipose to brown adipose, so you can turn it into metabolically active tissue. Then you're actually going to be able to burn more calories and you'll be way more metabolically active. You actually want brown fat. You can convert white fat to brown fat. You know, and that's probably does come down to—that's one of the things that when you looked at butyrate it was one of the places that butyrate actually worked was actually helping to convert more brown fat and white fat. So there was a big problem putting people on butyrate can really help with fat loss using butyrate and if you're overweight people who are all have metabolic their guts are horrible. Yeah, uterine those patients can really help with fat loss.  Lisa: I just had Dr Austin Perlmutter on you know, probably… And he was talking about the white fat cells, the visceral fat cells having not a consciousness but they have an ulterior motive to keep themselves alive. So they seem that all these—make you hungrier, send out inflammatory compounds and so on to make sure that they stay alive. They end up killing the host in the end. But like a cancer cell, they although they have their own agenda independent of what was actually healthy for your body. So they don't want you to do fasting. They don't want you to do any of these things, because they're not going to get knocked off.  Dr Yurth: Yeah, I mean, fat is metabolically active too. Remember it converts—fat cells have—they convert testosterone to estrogen. So men who are fatter will start converting all their testosterone into estrogen. So it's one of the places that that we have, you know, aromatase is inside fat cells. White men tend to have bigger breasts, and you know, is that fat cells actually are converting very mostly into this bad estrogen. So even your testosterone, you put them on testosterone, a lot of them just convert it to estrogen. Lisa: Wow. So that's independent of your innate genetic pathway for your hormones.  Dr Yurth: Fat cells have aromatase. Fat cells have aromatase. Lisa: Oh, wow, that's—I didn't realise that. I mean, I thought your genetic pathway was your genetic pathway. And you'll be converting your testosterone to estrogen is more if you have that genetic predisposition. Dr Yurth: It's certainly genetic there. But yes, that fat guys have breasts, right? You look at breasts because they're very estrogenic. And so if you try and get—if you take some of your overweight males, and you put them on testosterone without using things to block estrogen or getting rid of fat first, then you just keep making more estrogen, making more fat. They’re making it worse, right? Lisa: So okay, so it's not just to do with your genetic pathway, but also to do with how much fat you have. And the more fat tissue the more estrogenised you’ll be. That's in the new—okay. So that's why. Because you see, a lot of young people nowadays are thinking over probably growing up with less quality food than what we grew up with in our generation, seem to be more estrogenised and have more of these issues, and the actual body shape, the phenotype, the way it secretes, is this more estrogenised than past generations? Dr Yurth: We're seeing a lot of twenty-year olds who come in, who have high estrogen levels, low testosterone levels. I think drugs have to do with that, too. I mean, here in Colorado, we have legal marijuana, which is unfortunately not very good for testosterone.  Lisa: Oh, wow. I didn’t know that either. Marijuana is not good for testosterone.  Dr Yurth: It's not good for testosterone levels at all. And then our food, right, bisphosphonates all these things that are so we're seeing this you know, these really young guys with testosterone levels that that you're a god awful. Lisa: And then estrogen levels higher than the... Dr Yurth: Estrogen levels that are high, right?  Lisa: Yeah, I just did my estrogen levels and my—I know mine are low because I'm going through menopause and so on. And I was looking at my husband's and I was thinking, ‘Oh, it was about…’ Dr Yurth: You do start good to see that right. You start to see that these men—these older man look like woman, it switches. Yeah. You know, and they start taking on more female build, right? They get the bigger breasts and bigger bellies and they start getting this more female build to them.  Lisa: I mean, I've had lots of things so that it's not it's you, going the other way and there's testosterone is good and bad. Yeah, that is what you see in older and older men is that tendency to go and eat. It's really really hard to get testosterone replacement therapy or hormone replacement therapy for men or—for woman a little bit easier. They've seen you know, the doctor seems... I am willing to give it to woman but well, this integrated medical fraternity for bioidentical hormone replacement? And, you know, it's so easy... Dr Yurth: It kind of kills me because I get this—we're putting together this course called what to fix for us to kind of help people. In this journey of getting healthy, what do I do? Because I'm overwhelmed. And as I was putting together, I was like, ‘Okay, well, you start with exercise’. And that's it. No, actually, you kind of have to start with hormones. Because if I take somebody who has no testosterone, and no hormones, they have no progesterone, so they can't sleep, they have no testosterone, this is both men and women. So you know that their joints hurt, because there's progesterone receptors on joints, they've no testosterone. So trying to get them to go into the gym, and is impossible.  So for me to say, follow a good diet, do exercise without replacing hormones. It's really kind of not right, right. I mean, as I was putting together a talk, I said, you know, actually, the first thing I do is get these people hormone stabilised, because then I'm going to go to motivate another, their testosterone levels are good, they feel m

During Lucy’s first maternity leave, she felt alienated from her profession. People would tell her that she would lose interest in working full time but she didn’t. In her second MAT leave, she was determined not to be on the outside looking. While attending an event put on by the MPTP project, for the first time she became aware that she could go on school visits during her MAT leave. Over the next couple of months, Lucy goes on several school walk-throughs with her young child Roland. She learned a lot about how to make this happen and the benefits of visiting schools during her MAT leave. Frances Ashton is the Assistant Headteacher of Dicot Girls School, which is one of the schools Lucy listed. Frances tells us how to prepare for a school with a teacher on MAT leave. BIG Thank you to Lucy and Frances for sharing their story. This is the tweet Lucy sent to get this all started. Plus, her blog about this story on WAIB.   If you enjoyed this episode please share on Twitter, subscribe, and leave a comment It really means a lot Click here If you are interested in joining the We Are In Beta Community and/or the Curriculum Thinkers Community  Email our producer Jay@weareinbeta or fill out this submission form if you want to share your story on the podcast

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.20.392175v1?rss=1 Authors: Tokarew, J. M., El Kodsi, D. N., Lengacher, N. A., Fehr, T. K., Nguyen, A. P., Shutinoski, B., O'Nuallain, B., Jin, M., Khan, J., Ng, A. C. H., Li, J., Jiang, Q., Zhang, M., Wang, L., Sengupta, R., Barber, K., Tran, A., Zandee, S., Dong, X., Scherzer, C. R., Prat, A., Tsai, E., Takanashi, M., Hattori, N., Chan, J. A., Zecca, L., West, A., Holmgren, A., Puente, L., Shaw, G. S., Toth, G., Woulfe, J., Taylor, P., Tomlinson, J. J., Schlossmacher, M. G. Abstract: The mechanisms by which parkin protects the adult human brain from Parkinson disease remain incompletely understood. We hypothesized that parkin cysteines participate in redox reactions, which are reflected in its posttranslational modifications. We found that in human control brain, including the S. nigra, parkin is largely insoluble after age 40 years, which is linked to its oxidation, e.g., at Cys95 and Cys253. In mice, oxidative stress increases posttranslational modifications at parkin cysteines and reduces its solubility. Oxidation of recombinant parkin also promotes insolubility and aggregate formation, but in parallel, lowers hydrogen peroxide (H2O2). This thiol-based redox activity is diminished by parkin point mutants, e.g., p.C431F and p.G328E. Intriguingly, in parkin-deficient human brain H2O2 concentrations are elevated. In prkn-null mice, H2O2 levels are dysregulated under oxidative stress conditions, such as acutely by MPTP-toxin exposure or chronically due to a second genetic hit. In dopamine toxicity studies, wild-type parkin, but not disease-linked mutants, protects human dopaminergic M17 cells, in part through lowering H2O2. Parkin also neutralizes reactive, electrophilic dopamine metabolites via adduct formation, which occurs foremost at primate-specific Cys95. Further, wild-type but not p.C95A-mutant parkin augments melanin formation. In sections of normal, adult human midbrain, parkin specifically co-localizes with neuromelanin pigment, frequently within LAMP-3/CD63+ lysosomes. We conclude that oxidative modifications of parkin cysteines are associated with protective outcomes, which include the reduction of H2O2, conjugation of reactive dopamine metabolites, sequestration of radicals within insoluble aggregates, and increased melanin formation. The loss of these redox effects may augment oxidative stress in dopamine producing neurons of mutant PRKN allele carriers, thereby contributing to neurodegeneration. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.20.305375v1?rss=1 Authors: Mailman, R. B., Yang, Y., Huang, X. Abstract: Levodopa is the Parkinson's disease standard-of-care, but continued loss of dopamine neurons with disease progression decreases its bioconversion to dopamine, leading to increased side effects and decreased efficacy. In theory, dopamine agonists could equal levodopa, but no approved oral "dopamine agonist" matches the efficacy of levodopa. Although there are consistent data in both primate models and in Parkinson's disease showing that selective high intrinsic activity D1 agonists can equal levodopa, there are no data on whether such compounds would be effective in severe disease when levodopa efficacy is lower or even absent. We compared two approved antiparkinson drugs (levodopa and the D2/3 agonist bromocriptine) with the experimental selective D1 full agonist dihydrexidine in two severely parkinsonian MPTP-treated non-human primates. Bromocriptine caused no discernable improvement in parkinsonian signs, whereas levodopa caused a small transient improvement in one of the two subjects. Conversely, the full D1 agonist dihydrexidine caused a dramatic improvement in both subjects, decreasing parkinsonian signs by ca. 75%. No attenuation of dihydrexidine effects was observed when the two subjects were pretreated with the D2 antagonist remoxipride. These data provide evidence that selective D1 agonists may provide profound antiparkinson symptomatic relief even when the degree of nigrostriatal degeneration is so severe that current drugs are ineffective. Until effective disease-modifying therapies are discovered, high intrinsic activity D1 agonists may offer a major therapeutic advance in improving the quality of life, and potentially the longevity, of late stage Parkinson's patients. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.16.206094v1?rss=1 Authors: Goksu Erol, A. Y., Akinci, E., Kocanci, F. G., Akcakale, F., Demir Dora, D., Uysal, H. Abstract: Introduction: Microglia secretome includes not only growth factors and cytokines which support neuronal survival, it includes neurotoxic cytokines/enzymes, as well. MPTP is a neurotoxin which has degenerative effects on SH-SY5Y neuroblastoma cells. Masitinib mesylate is a tyrosine kinase inhibitor which has been shown to have beneficial effects in neurodegenerative diseases. Aim : We first aimed to determine the most efficient microglial cell conditioned medium in terms of neurodegenerative effect. Next, we investigated the possible protective/therapeutic effects of masitinib against MPTP/microglia-induced degeneration of differentiated ( d )-SH-SY5Y cells, and the role of transforming growth factor (TGF)-b1 and nitric oxide (NO) in these events. Material-Methods : Non-stimulated/LPS-stimulated microglia cells were treated with masitinib or its solvent, DMSO. With or without MPTP- d -SH-SY5Y cell cultures were exposed to the conditioned media (CM) from microglia cell cultures, followed by cell survival analysis. Immunofluorescence staining of microglia and d -SH-SY5Y cells were performed with anti-CD-11b and anti-PGP9.5 antibody, respectively. TGF-b1/NO concentrations in CM of microglia/ d -SH-SY5Y cell culture were measured. Results: The initial 24 hrs CM of non-stimulated microglia cell culture was found to be the most detrimental microglial medium with lowest survival rates of treated d -SH-SY5Y cells. The toxicity of 48 and 72 hrs CM on d -SH-SY5Y cells were both lower than that of 24 hrs CM. Masitinib (0.5 {micro}M), significantly prevented MPTP-related cell degeneration of d -SH-SY5Y cells. It also decreased the degenerative effects of both non-induced/LPS-induced microglia CM on with or without MPTP- d -SH-SY5Y cells. Although NO levels in microglia CM showed a negative correlation with survival rates of treated d -SH-SY5Y cells, a positive correlation was seen between TGF-{beta}1 concentrations in microglial CM and rates of treated d -SH-SY5Y cell survival. Conclusion : Masitinib ameliorates viability of with/without MPTP- d -SH-SY5Y cells. It does not only reverse the degenerative effects of its solvent, DMSO, but also prevents the degenerative effects of microglial secretions and MPTP. We suggest that masitinib begins to act as a neuroprotective agent via mediating TGF-b1 and NO secretion, as neurons are exposed to over-activated microglia or neurotoxins. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.16.144477v1?rss=1 Authors: Johnson, L. A., Aman, J. E., Yu, Y., Escobar Sanabria, D., Wang, J., Hill, M., Dharnipragada, R., Patriat, R., Fiecas, M., Li, L., Schrock, L. E., Cooper, S. E., Johnson, M. D., Park, M. C., Harel, N., Vitek, J. L. Abstract: Abnormal oscillatory neural activity in the basal ganglia is thought to play a pathophysiological role in Parkinson's disease. Many patient studies have focused on beta frequency band (13-35 Hz) local field potential activity in the subthalamic nucleus, however increasing evidence points to alterations in neural oscillations in high frequency ranges (>100 Hz) having pathophysiological relevance. Prior studies have found that power in subthalamic high frequency oscillations (HFOs) is positively correlated with dopamine tone and increased during voluntary movements, implicating these brain rhythms in normal basal ganglia function. Contrary to this idea, in the current study we present a combination of clinical and preclinical data that support the hypothesis that HFOs in the internal globus pallidus (GPi) are a pathophysiological feature of Parkinson's disease. Spontaneous and movement-related pallidal field potentials were recorded from deep brain stimulation (DBS) leads targeting the GPi in five externalized Parkinson's disease patients, on and off dopaminergic medication. We identified a prominent oscillatory peak centered at 200-300 Hz in the off-medication rest recordings in all patients. High frequency power increased during movement, and the magnitude of modulation was negatively correlated with bradykinesia. Moreover, high frequency oscillations were significantly attenuated in the on-medication condition, suggesting they are a feature of the parkinsonian condition. To further confirm that GPi high frequency oscillations are characteristic of dopamine depletion, we also collected field potentials from DBS leads chronically implanted in three rhesus monkeys before and after the induction of parkinsonism with the neurotoxin 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP). High frequency oscillations and their modulation during movement were not prominent in the normal condition but emerged in the parkinsonian condition in the monkey model. These data provide the first evidence demonstrating that exaggerated, movement-modulated high frequency oscillations in the internal globus pallidus are a pathophysiological feature of Parkinson's disease, and motivate additional investigations into the functional roles of high frequency neural oscillations across the basal ganglia-thalamocortical motor circuit and their relationship to motor control in normal and diseased states. These findings also provide rationale for further exploration of these signals for electrophysiological biomarker-based device programming and stimulation strategies in patients receiving deep brain stimulation therapy. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.04.26.062380v1?rss=1 Authors: El Kodsi, D. N., Tokarew, J. M., Sengupta, R., Lengacher, N. A., Ng, A. C., Boston, H., Jiang, Q., Palmberg, C., Pileggi, C., Shutinoski, B., Li, J., Nguyen, A. P., Fehr, T. K., Im, D. S., Callaghan, S., Park, D. S., LaVoie, M. J., Chan, J. A., Takanashi, M., Hattori, N., Ratan, R. R., Zecca, L., Puente, L., Shaw, G. S., Harper, M.-E., Holmgren, A., Tomlinson, J. J., Schlossmacher, M. G. Abstract: We recently hypothesized that parkin plays a role in redox homeostasis and provided evidence that it directly reduces hydrogen peroxide (H2O2) in vitro. Here, we examined this anti-oxidant activity in vivo. Informed by findings in human brain, we demonstrate that elevated oxidative stress promotes parkin insolubility in mice. In normal mouse brain parkin was partially oxidized, e.g., at cysteines 195 and 252, which was augmented by oxidative stress. Although under basal conditions H2O2 levels were unchanged in adult prkn-/- brain, a parkin-dependent reduction of cytosolic H2O2 was observed when mitochondria were impaired, either due to neurotoxicant exposure (MPTP) or Sod2 haploinsufficiency. In accordance, markers of oxidative stress, e.g., protein carbonylation and nitrotyrosination, were elevated in the cytosol but not in mitochondria from prkn-/- mice. This rise in oxidative stress was associated with altered glutathione homeostasis. In parkin's absence reduced glutathione concentrations were increased in cells, murine brain and human cortex. This compensation was not due to new glutathione synthesis but attributed to elevated oxidized glutathione (GSSG)-reductase activity. Moreover, we discovered that parkin also recycled GSSG to its reduced form. With this reaction, parkin became S-glutathionylated, e.g., at cysteines 59 and human-specific 95. This oxidative modification was reversed by glutaredoxin. Our results demonstrate that cytosolic parkin mediates anti-oxidant reactions including H2O2 reduction and glutathione regeneration. These reducing activities lead to a range of oxidative modifications in parkin itself. In parkin-deficient brain oxidative stress rises despite changes to maintain redox balance. Copy rights belong to original authors. Visit the link for more info

What are the different possible triggers for how people get Parkinson’s? Find out in this episode as I try to narrow down how the degenerative brain disorder was unleashed on me. After Niki and I chat about the “how,” my wife ,Rebecca and I begin to explore the “why?” If you have Parkinson’s, you may want to play along at home while you listen. Here’s a handy check list to see what factors potentially triggered your onset of PD. Check ALL that apply: I am male. I am older than 60 years old. I have parents or siblings who have Parkinson’s disease. Genetic tests show I carry a gene that is associated with the onset of Parkinson’s disease. Genetic tests show I carry a gene that is associated with brain degeneration. I play or played a high contact sport (Football, Hockey, Rugby, Boxing, Martial Arts) I have played or played high contact sports for more than eight years. I have experienced several concussions. I live or have lived near a major, busy road. I have worked or lived near a chemical plant. I have suffered Agent Orange exposure. I have been exposed, over a long period time or at extremely high levels to pesticides. I have been described as a workaholic, a Type-A personality, or stressed-out. I do not exercise. I have had a stroke. I have injected the MPTP strain of synthetic Heroin and suffered spontaneous Parkinson’s. I was born with damaged dopamine-producing brain cells. I died. During my autopsy, Alpha-Synuclein was discovered clumping in my brain (Lewy Bodies). I did not realize how much I was asking myself, “What did I do to get Parkinson’s?” until I started putting together this episode. The recent study by Cedars-Sinai Hospital in California that we discuss at the end of the episode was a real revelation for me. It suggests that people with Young Onset Parkinson’s may be born with malfunctioning dopamine producing brain cells, which leads to the clumping of the protein Alpha-Synulcein (Lewy bodies) and ultimately leads to the onset of Parkinson’s disease. In the episode, we hear from many qualified professionals about different reasons how Parkinson’s onsets. Sohini Dhowdhury, Deputy CEO of The Michael J. Fox Foundation, discusses why she is so interested in Alpha Synuclein research. “We know it’s the hallmark of Parkinson’s. Research and therapies targeting this protein gets to the root biological process,” Chowdhury said.   At UCLA, Dr. Jeff Bronstein, the head of the movement disorder clinic there and Dr Beata Ritz, professor of epidemiology at Fielding School of Public Health, collaborate on environmental factors that could trigger the onset of PD, like pesticides, both for the home and industrial use. Dr. Ritz has little doubt when she speaks on this topic, “Some pesticides are neurotoxic in a way that causes Parkinson’s disease when you are exposed over a very long time or very high levels.” In the episode, we examine the herbicide Paraquat, which is banned in many countries around the world, yet remains one of the most widely used chemicals to protect crops. There are many ways people can trigger Parkinson’s and many reasons why someone is diagnosed with it. Dr. Bronstein believes every case is unique, “I think of it as a humungous Venn diagram in which there and many, many different factors.” In the end, how I got Parkinson’s may not matter to anyone else, but me. But, for me, I’d be more comfortable knowing it was hibernating within me until I was ready for it, instead of me doing something to unnaturally cause it. In reality, I’ll likely never know what combination of things unlocked this disease. On the flip side, it’s brought me as much joy, friendship, perspective, and purpose in life  – and maybe more – than any one thing in my life. Feel free to comment by leaving us a voice message here: https://www.speakpipe.com/WhenLifeGivesYouParkinsons Follow me, Larry Gifford  Twitter: @ParkinsonsPod Facebook: Facebook.com/ParkinsonsPod Instagram: @parkinsonspod Follow Co-host and Producer Niki Reitmeyer Twitter: @Niki_Reitmayer Thank you to our special guests:  Dr. Jeff Bronstein, Head of the Movement Disorder Clinic at UCLA Dr. Beata Ritz, professor of Epidemiology at Fielding School of Public Health, Dr. Malu Tansey, Director, Center for Translation Research in Neurodegenerative Disease Dr. Matt Farrer, Program Director, Nuerology & Movement Disorders at University of Florida Michael Brauer, professor, UBC school of population and public health Sohini Chowdhury, Deputy CEO of The Michael J. Fox Foundation Marty Gifford Rebecca Gifford The book referred to in the podcast was “The Case of the Frozen Addicts.” Our presenting partner is Parkinson Canada http://www.parkinson.ca/ The toll free hotline 1-800-565-3000 Follow them on Twitter @ParkinsonCanada Find the new Parkinson Clinical Guideline www.parkinsonclinicalguideline.ca Thanks also to our content and promotional partners Parkinson’s IQ + You– A free, series of Parkinson’s events from the Michael J. Fox Foundation Spotlight YOPD – The only Parkinson’s organization dedicated to raising awareness for Young Onset Parkinson’s disease and funds for the Cure Parkinson’s Trust. 

On this inaugural episode of MPtP, I talk about one of my favorite films this year, The Rider, directed by Chloe Zhou.

The Victorian Government is reviewing the Multi Purpose Taxi program and considering how to improve transport for people with limited mobility.Raising Our Voices discusses the review and shares some ideas on how the system could be improved.To have your say visit the consultation page . http://economicdevelopment.vic.gov.au/transport/rail-and-roads/taxis/multi-purpose-taxi-program-review/get-involved-in-consultation.Consultation for the review runs from Tuesday 29 September 2015 to 5pm Friday 4 December 2015  Anyone with an interest in the Multi Purpose Taxi Program or improving transport for mobility limited Victorians is encouraged to participate in this consultation. This includes MPTP program users, carers, disability advocacy groups, and the taxi and hire car industry.

MDS presents the latest research and findings from the field of Movement Disorders. Abstracts of articles from the Society Journal, Movement Disorders, are taken from the December 2013 (Vol. 28, Issue 14) issue.

Geoff Butcher has Parkinson's disease. Here we hear him interview a scientist who uses Marmosets as an animal model to investigate Parkinson's disease. The scientist does this by using a chemical called MPTP to destroy the substantia nigra in the Marmosets. This is the part of the brain that is associated with the fine control of movement. It is damage to the substantia nigra that caused the symptoms of Parkinson's disease. The discovery of MPTP was an accident. Drug-users took contaminated material and developed Parkinsonian-like symptoms. This led to the unravelling of a medical mystery described in The Case of The Frozen Addicts reviewed here: http://www.nejm.org/doi/full/10.1056/NEJM199612263352618

Dr. Joe Hickey, MD, discusses the approach he uses in his practive to treating the symptoms of Parkinsons disease. Many standard medical tests do not detect the presence of toxins embadded in the tissues and organs of the body. Environmental toxins are presumed to be the triggers for development of Parkinson’s Disease.  Examples of toxins as the cause of PD have been well documented such as Manganese toxicity, Carbon Monoxide poisoning, Carbon DiSulfide from the Rayon Industry and MPTP.  He will add to this list, environmental exposures such as aluminum, lead, and mercury.