BDNF: How To Teach An Old Dog New Tricks

Episode 101

Strive for Great Health Podcast Episode 101 – BDNF: How To Teach An Old Dog New Tricks

Brain health fascinates me. I was raised in a house full of mental illness and saw two grandparents pass away from neurodegenerative disorders (Alzheimer’s and Parkinson’s). Brain-derived neurotrophic factor (BDNF) is one of the critical regulators of brain health by controlling neuroplasticity. Our brain can adapt to our ever-changing environment and has a remarkable ability to heal when placed in the right situation. Episode 101 dives into BDNF and leaves you with actionable tips to enhance your brain health.

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Episode Transcript

Dr. Richard Harris MD  00:00

Welcome to another episode of The strive for greater health podcast with your host, Dr. Richard Harris. And we’re going to be talking about something that I’m very interested in and that is brain health, specifically brain derived neurotrophic factor or BD in F. This is something that’s very important to me as a carrier have one of the strongest genetic risk factors for Alzheimer’s. So we’re gonna dive into what BDNF is, what it does, how its regulated in ways that you can improve your brain health by increasing BDNF. Are you ready to boost your health, EQ and IQ? Cue the music?

Dr. Richard Harris MD  00:50

Join me Dr. Richard Harris as we strive to unlock the secret to the human body. Strive for Wellness strive for great health. Follow the show on iTunes, Spotify, Google and Android.

Dr. Richard Harris MD  01:16

Now a word from our sponsors. Our first sponsor is Nimbus healthcare, the company that I co founded personalized medicine personalized results. At Nimbus. We don’t believe that there’s a one size fits all when it comes to treatment. And the data is starting to show that there’s a large variety of how people respond to certain things. And we’re in the Age of Science where we can use things like genetic testing and biomarkers to truly customize a plan just for you. And that’s what we do at Nimbus healthcare. We are in the hair loss and the hormone space. And what we do is we use lifestyle medicine, supplements and compounded prescription medication to tailor and individualize a plan just for you. If that sounds like something that you’re looking for, you can check out Nimbus or click the link in the show notes. Our other sponsor is CBD health collection. CBD health collection is the CBD that we use in the house. We use it. Our dog uses it love CBD health collection, it meets all of the requirements that we set forth in our CBD episode, organic us grown. They do a lot of third party testing so you know exactly what you’re getting in the product. And it works. My ordering data is wonderful when I take the product for sleep, and then I also use it for inflammation and recovery. If you’re looking for a high quality CBD that is third party independently tested and who does research they work with universities to do research on their products to push the edge on CBD and make sure they’re staying current. Then CBD health collection is the CBD for you. You can check the link in the show notes or head to our website, the GH and click CBD at the top. And now to this week’s episode. What is beautiful people welcome back to another episode of The strive for great health podcast. We’re talking about brain health today and specifically, BDNF. We’re going to do a deep dive on BDNF and of course at the end, we’re gonna give you practical tips on how you can improve your brain health by increasing BDNF that’s been proven in human trials. Let’s dive right in. First thing.

Dr. Richard Harris MD  03:27

What is BDNF? BDNF is a molecule involved in neuroplasticity, we’ve talked about neuroplasticity In fact, I gave a talk on this recently and I called it how you teach an old dog new tricks. Because that is the essence of neuroplasticity is how our brain is able to change and adapt. BDNF is related to learning and memory, and memory consolidation and discrimination of similar memories. The highest levels are in structures associated with memory. So the hippocampus also motion the cerebellum, executive function, the cortex, and emotional processing the amygdala. These are all areas that we’ve talked about before, except for the cerebellum, I think, but that’s an area of motion in the brain. The highest levels are in the hippocampus. But BDNF is also detected in other organs like the heart, the liver, the lungs, and spoiler alert the muscles we’ll talk about that more later. And BDNF is actually made as a precursor. There’s row, BDNF and BDNF. So actually, both are secreted at the same time and they have different functions and bind the different receptors. Grow BDNF is associated with cell death and long term depression, which means weakening connections between neurons through activation of something called the P 75. receptor. And something that we’ve talked about a lot on the podcast and f k b, which is that master pro inflammatory switch B BDNF is associated with self survival, long term potentiation, which is increasing connection between neurons. It’s also associated with increasing the complexity of neural spines. These are parts of the nerve cell increases the number and the size of the dendritic spines and their overall complexity. And this works through something called the track B receptor. Nerve cells are broken up into three main parts. You have the dendrite these are where the signals are received for that cell. There’s the axon, which sends the signals to other nerve cells, and then there’s the cell body where the metabolism happens. Pro BDNF is turned to BDNF either inside or outside the cell in our blood. BDNF is stored in platelets, where it can release where needed about 100 to 1000 times more concentrated in the platelets that a nerve cell so platelets serve as our reservoir of BDNF, and it’s estimated that 70% of circulating BDNF is stored in the platelets. How is BDNF involved with plasticity. BDNF is involved with trafficking so moving of receptors and other proteins, phosphorylation which is turning proteins on or off depending on where you do this and how you do it. It’s attaching phosphate groups and expression of an NMDA receptors. NMDA receptors are very important in the hippocampus, and they’re involved with long term potentiation and memory. Trafficking. We already talked about that a little bit. It’s the movement of cell membrane receptors and proteins specific locations. It’s important in maintaining proper nerve cell shape and function. deficits and tracking are associated with neurodegenerative diseases and Autism Spectrum Disorder. phosphorylation is adding phosphate groups to proteins they can turn them on or off an NMDA receptors activation of NMDA receptors causes calcium to enter the cell and you activate something called the ER KCR EB pathway in this actually activates BDNF expression. What controls BDNF expression BDNF expression is regulated by epigenetic, so environmental and genetic mechanisms. There is one gene of interest that has some data behind it, it’s called vow 66 met. And this polymorphism is involved in about 30% of people and a European population in one study were carriers. This affects the release of BDNF. It leads to lower serum BDNF levels, is associated with structural differences in the brain, loss of volume in the hippocampus, and also the parahippocampal gyrus, this area’s important in learning in processing of spatial configurations. It’s also important in emotional processing through connections to the limbic system, and then contextual associations like sarcasm in the right parahippocampal gyrus. There’s also in association of loss of volume in the prefrontal cortex and amygdala. People tend to do worse on performance and mnemonic and verbal tasks with short and long delays and deficits and working in spatial memory tasks. 2011 study and middle age pilots found that carriers have more age related skill decline and decrease in hippocampus volume than non carriers. Other studies and made analysis found no difference in cognitive ability memory, executive function, visual processing and cognitive fluency. The difference is likely due to epigenetic factors and unmeasured variables like physical activity, which is a key theme in this podcast that your genetics may say you’re more predisposed to something but you can moderate some or all of that risk based upon your lifestyle. Now we’re going to talk about some of the things that can affect BDNF. One of the biggest factors is aging. We have a pronounced decline in BDNF around 65. And you see that most cognitive decline starts around 70. Aging is associated with development of cognitive disorders, likely due to reduction in metabolic capacity and reduction in synaptic plasticity, aging causes shrinkage of gray matter, reduction in synapses and a reduction in other neuroplasticity related proteins. The hippocampus one of the key areas from memory is very sensitive to these changes, but other memory structures like the frontal and internal cortex, show volume reduction as well with aging BDNF and long term potentiation. And another area of the brain called the dentate gyrus is impaired. circulating levels of BDNF are decreased in aging humans, primates and a rat and this is also accompanied by a reduction in the BDNF receptor and an increase in pro BDNF and its receptor so favorite, the pro beat Enough which causes cell death and long term depression. In rats. fear conditioning is altered as the age as well suggesting that aging decreases BDNF in resting conditions and in response to specific stimuli. Other studies have found no change or an increase in BDNF with aging. There’s a couple of caveats here is that in humans, we can’t measure brain BDNF levels. No one’s signing up for Brain sampling while they’re alive. BDNF probably can pass through the blood brain barrier, so

Dr. Richard Harris MD  10:30

we use serum levels as a surrogate for brain levels. In animal models brain BDNF correlates with serum BDNF. Another possible cause for the discrepancy is measuring mature BDNF versus pro BDNF. A lot of the older assays couldn’t tell the difference. BDNF activation protein, so what changes pro BDNF to BDNF like TPA decrease over time, meaning you get more pro BDNF and less BDNF. Another reason is that BDNF can increase during oxidative stress, and it’s part of the antioxidant defense during aging. We’ll talk about this more in a minute. But when you initially have an insult, your body tries to repair and the insult to the brain, your body tries to repair by increasing BDNF. Another factor is genetic variability. genetic variability and cognitive decline may account for as much as a third of the variance in cognitive decline. For example, people with the APR II four gene is associated with declines in cognitive performance with aging. However, overall, the APR II and BDNF polymorphisms are thought to only account for about 2.3% of the variance and cognitive decline. And we know the effect of even the Met allele that we talked about earlier can be offset by exercise, and likely other epigenetic factors. What else BDNF levels change in neurodegenerative diseases and psychiatric diseases. We find lower BDNF levels are reported in diseases like Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and in Alzheimer’s disease. We show changes in the hippocampus, the parietal, the inter Ohio and the frontal cortex and BDNF levels in Huntington’s disease in the striatum in the motor cortex, post mortem. So after people have passed away studies in Alzheimer’s, and mild cognitive impairment show lower BDNF levels, lower BDNF mRNA. So the protein that actually tells the cells machinery to make BDNF and then pro BDNF compared to controls with no change in receptor levels, BDNF levels seem to correlate with severity of Alzheimer’s disease. Earlier and Alzheimer’s disease BDNF levels are actually higher. This is like the brain trying to combat the D generative changes that are seen and some studies show higher levels of BDNF and BDNF receptors in the hippocampus and the parietal cortex. Again, these differences are likely due to lots of factors lifestyle, diagnostic criteria age, the stage of disease, sex education, and then there are medical treatments that actually raise BDNF.

Dr. Richard Harris MD  13:19

beta amyloid, we’ve talked about this before the plaques that form and Alzheimer’s disease has antimicrobial properties and helps to regulate synaptic function. So some beta amyloid good lots of beta amyloid bad. In Alzheimer’s disease BDNF protects against amyloid plaque toxicity by enhancing degradation of the amyloid plaques and preventing tau hyperphosphorylation. We talked about that in the Alzheimer’s podcast. These beta amyloid plaques down regulate BDNF and disrupt its transport and prevents conversion of pro BDNF, the BDNF. What we’re seeing overall is as these plaques develop, we’re getting a decrease in BDNF development. Polymorphism has mixed results on increasing Alzheimer’s disease risk, carriers may have a greater decline and episodic memory and hippocampal atrophy with mild cognitive impairment. Higher levels of BDNF are associated with protective effect against dementia and Alzheimer’s disease and predicts slower rates of decline. And this is true in one study whether it was pharmacologic, or exercise induced BDNF changes, psychiatric diseases. Post Mortem studies show lower levels of BDNF in the hippocampus and the prefrontal cortex and patients with bipolar disorder and major depression. Levels of serum BDNF correlate with duration of manic and depressive episodes. So what’s interesting is that the level is lower when they have these manic or depressive episodes and come up when they’re in remission. Patients with bipolar disorder and the Valmet polymorphisms show that BDNF levels correlate with episodic memory and high levels of serum BDNF are associated with good cognitive performance. And schizophrenia studies show an increase. Others show a decrease in prefrontal cortex and hippocampus levels of BDNF. One study found that a 12 week treatment with olanzapine which is an anti psychotic medication, increased plasma BDNF concentrations, and this increase correlated with cognitive performance. And BDNF has also been studied in depression. And BDNF regulates the growth and reconstruction of serotonin nerve terminals in the cortex. We talked about serotonin before. A lot of the medications for depression work on increasing serotonin but these antidepressants also increase BDNF. Administration of BDNF and rats reduces depressive symptoms, and serum BDNF is decreased in patients with major depression. Chronic inflammation reduces BDNF we’ve talked about inflammation and the effects on the brain. There’s an inverse association here, the more inflammation the more oxidative stress the lower the BDNF. This is why when people are going through very strenuous bouts of inflammation, let’s say COVID. What did we talk about COVID brain fog. People with autoimmune disease where do they talk about brain fog? Because there’s inflammation in the body but the brain is not disconnected from the body. If there’s systemic inflammation, your brain is going to feel those effects. pro inflammatory mediators like il six and TNF from the microglia microglia are immune cells in the brain. These things decrease neuroplasticity by reducing BDNF. BDNF is also lowered by chronic stress. We know that chronic stress causes chronic inflammation. Chronic stress decreases BDNF in the hippocampus, it suppresses that long term potentiation. My study showed improvement in BDNF levels after stress with exercise in animal models enriching the environment. So giving the mice like a mice Hilton kind of getaway type of thing was as effective as fluoxetine, which is a an antidepressant medication that works on serotonin in a chronic stress protocol. Both the fluoxetine and the environmental enrichment increase BDNF in the hippocampus of rats. Low levels of BDNF are associated with people who binge drink lower BDNF levels are also associated with metabolic syndrome. We’ve talked about metabolic syndrome before body mass being overweight or obese insulin resistance, high blood pressure, abnormal lipids, lower BDNF levels are associated with overeating with obesity and reduced satiety. Let’s talk about how do we increase BDNF exercise both aerobic and strength training increases BDNF. We know from studies that exercise improves learning improves memory, prevent structural changes and structural decline in the brain

Dr. Richard Harris MD  18:02

and protects against age related cognitive decline. In one study, high intensity interval training exercise was better than continuous exercise and healthy subjects. They use a hip protocol that was 10 cycles. And what they did was 60 seconds on 60 seconds off. And they did this three days a week for four weeks. We know that muscle contraction stimulates certain genes, and you get an increase and BDNF and this is likely through a gene called F and D. C. Five BDNF levels elevate after acute bouts of exercise, but to get consistent elevation. It takes a few weeks. And so what happens is you exercise BDNF levels will come up for a couple of days and oh come down, but to consistently stay up. It takes a few weeks of consistent exercise. So exercise seems to give a dose of BDNF and over time that dose is enhanced to where you can maintain higher levels of BDNF through consistent exercise. One of the things that is important is intensity matters. So low intensity cardio low intensity strength training does not efficiently stimulate BDNF do you need higher intensity. So that’s why the high intensity interval training and more intense strength training so training within a couple reps of failure training to failure does stimulate BDNF stress mitigation increases BDNF. One study found that BDNF increase three fold. So three times increase in BDNF after a mind body retreat, with about five hours of combined mindfulness daily. Our thoughts and experiences regulate BDNF exposure to novel experiences increases BDNF, so things like travel things like picking up new skills. Why? Because your brain has to change and adapt to the new environment. We couldn’t learn new skills if our brain didn’t To death, if I go drop you in a foreign country, you need a new routine, you need to figure things out. So your brain increases BDNF, to help you figure things out and to learn your new environment. This is why novel experiences trying new things, picking up new hobbies, and travel are so important to our overall health. And this also from a mechanistic standpoint makes sense. Because as we get novel experience, this is a dopamine system thing. So we increase dopamine with novel experiences in dopamine activation increases BDNF in the prefrontal cortex to improve your metabolic health. I don’t even know how many times we’ve talked about metabolic health on this podcast and improving metabolic health. A study recently showed that only 6.9% of Americans have good cardio metabolic health. That’s just sad. One study found in those with metabolic syndrome, a 20% increase in BDNF with carbohydrate restriction, so about 15% of their calorie intake from carbs, and then they found a 38% increase in BDNF with carb restriction and hip exercise. The study actually induce ketosis in participants. And animal studies have shown that ketosis can increase BDNF levels, likely because ketosis inhibits something called Ajax Ajax what they do is they normally suppress BDNF, so turning them off increases BDNF threat. Studies show a high fat high refined sugar typical of a Western diet is associated with lower BDNF and fasting. One study showed a 48 hour fast increase BDNF levels by three and a half times and this is likely due to inducing ketosis which stimulates BDNF. What we do is we try to do a 48 hour electrolyte and ketone fast, once a quarter, and we do our 24 hour fast every Sunday. Social interaction, social interaction has been shown to improve learning improve memory, and guess what? Improving learning and memory typically goes with increased BDNF. Social isolation, lowers BDNF, so getting a group we’ve talked about this so many times on the podcast before estrogen estrogens regulate BDNF, and what happens is you get a change in BDNF levels in the cycle. In the luteal phase of the menstrual cycle, BDNF peaks, then it goes down again, then peaks again mid luteal phase, and this actually corresponds to estrogen peaks.

Dr. Richard Harris MD  22:46

And BDNF levels seem to correlate quite strongly with both estrogen and progesterone levels. The correlation coefficient for estrogen is point eight, which is a very high correlation coefficient. And for progesterone, it’s point seven. We know that BDNF levels drop in women who do not ovulate and during menopause. There was one study that looked at hormone replacement therapy, and hormone replacement therapy can restore BDNF levels to those seen in the follicular phase of ovulation. This study use two milligrams of estradiol for 16 days followed by two milligrams of extra dial and 0.075 milligrams of lipo gestural, it’s a type of progression for 12 days for six months, and they found an increase in BDNF. It’s speculated that estrogen and progesterone have protective effects on the brain due to BDNF. And what you see as you see a high colocalization of estrogen receptors and BDNF receptors in the brain. And estrogen seems to have similar functions and modulation of NMDA receptors and memory, increasing dendritic spine and Synapse number, pregnancy and postpartum are associated with lower BDNF levels. And it’s speculated that this may contribute to postnatal mood disorders. Now, what about testosterone? Testosterone? The waters are a little bit muddier. There’s some evidence in rats, testosterone increases BDNF in some areas of the brain. It decreases it in others. Testosterone we know does impact neurogenesis and making new nerve cells. It seems to help protect the brain and models of stroke and trauma. And it may do so through a pathway not related to BDNF. There’s something called the map que pathway. What is likely happening with testosterone is that testosterone is increasing BDNF through an indirect effect by conversion to estradiol. In animal models stimulation of the ECS, our old friend the endocannabinoid system increases BDNF, and this is thought to be due because endocannabinoids increase a certain type of serotonin called Five HD one a level roles and activation of the cannabinoid one receptor in the cannabinoid two receptor are involved in neurogenesis and dendritic modeling. There’s only one human study I found and it was in Parkinson’s patients, and they had six weeks of placebo, six weeks of CBD 75 milligrams per day and 300 milligrams per day. And they found no difference in BDNF, but they did found significant improvement in quality of life and well being. And the patients had Parkinson’s for about an average of eight years beforehand. So this might be something that might be more effective early on in the disease state. What else sun exposure? Well, we’ve talked about how sun exposure increases serotonin and serotonin is very important for BDNF. So sun exposure should increase BDNF, and this has been shown BDNF levels show a seasonal variation, their higher in the summer and lower in the winter. And it actually correlates with the amount of ambient sunlight so the more sunlight you get safely, the higher the BDNF levels, and then you also want to regulate inflammation, you want to increase your poly phenols your antioxidants butyrate, like we’ve talked about from certain gut bacteria, gut bacteria will take up fiber and turn it into the short chain fatty acids, your gut bacteria will take up poly phenols and turn them into certain neuromodulators. So reducing inflammation regulating inflammation through what we eat by increasing poly phenols, increasing antioxidants, increasing fiber, this can all have a positive effect on BDNF. Let’s talk about supplements because there’s a lot of supplements that say they increase BDNF, and a lot of it is based on rat studies. Rat studies don’t always correlate to human data. And there’s lots of reasons for that. Typically, the dosages and rat studies are really high. They’re not the same as dosages used in human studies. So either way, the rat studies don’t always correlate with human studies. So what are some ways that I can increase BDNF through supplementation found in human studies? Coffee fruit, coffee, fruit extract is a great source of polyphenols. In one study, 100 milligrams of coffee fruit extract compared to placebo, and they also had a third group of other caffeine extracts. The coffee fruit increased BDNF levels by 143% during the first 60 minutes after treatment for healthy subjects, another one and one of our favorites. Cacao dark chocolate. It contains lots of flavonoid antioxidants, including theobromine. theobromine, is chemically very similar to caffeine.

Dr. Richard Harris MD  27:46

This likely works because of antioxidant effect antioxidants up regulate BDNF. Cacao may also directly activate pathways that increase BDNF synthesis, that er K creb pathway that talked about earlier. There’s a study that had people drink a cacao drink containing 494, which about two tablespoons of unsweetened cacao powder for 34 milligrams of flavonols over 12 weeks, and it showed an increase in BDNF compared to low flavonol intake controls, and brain function testing the high intake flavonols is associated with cognitive improvements. What else carotenoids these are the naturally occurring antioxidants that are found in fruits and veggies and the yellow orange color. likely increase BDNF by reducing inflammation and activating BDNF production. There’s one study using a combination of 13 milligrams of lutein Xanthine and measles Xanthine in healthy subjects. And these were young, these are people 18 to 25. For 12 weeks versus placebo, they found an increase in BDNF. So whenever I see a study that shows that you can increase something in young healthy volunteers. That gets like ding ding, ding, ding, ding, ding, ding, right. They also found a decrease and an inflammatory marker, il one, they found an increase in composite memory, verbal memory, sustained attention, psychomotor speed and processing speed. All of these things were unchanged in the placebo group. So that’s a pretty exciting study. What else fish oil. Fish oil works by increasing BDNF likely in two ways by increasing BDNF production and enhancing the effect of BDNF. One study had people with schizophrenia tick 2.2 grams of fish oil a day versus placebo. And they did levels at eight and 26 weeks later, and they found BDNF levels were higher. Another study and traumatic brain injury patients with 1.47 grams of DHA plus 147 milligrams of EPA for 12 weeks versus placebo, did not see any difference between the groups. This is likely due to the population study we talked about earlier that BDNF increases on it is own after traumatic injuries, and also the cohort was in Japan and people in Japan regularly consume higher levels of seafood. They have higher levels of Omega three intake. Both studies, however, show that higher levels of BDNF were associated with lower depressive symptoms. Curcumin, curcumin likely increases BDNF by lowering inflammation. It also has antioxidant properties, and it aids with the body’s stress response. It may also activate cellular signals that increase BDNF production, or it may work through an increase in serotonin. So there was a meta analysis from 2019. It looked at doses between 212 180 milligrams of curcumin per day, and they found a small increase in BDNF levels. And people who took curcumin there were certain subgroups that there was no significant effect and that was men younger than 40. And then for doses less than 500 milligrams a day. They also found no effect for people who use it for less than eight weeks. Another study looked at obese people, and they used doses between 500 to 750 milligrams for 12 weeks and found no difference in BDNF levels. But they did find that curcumin decrease protein and lipid oxidation which is a good thing, zinc, 30 milligrams of zinc daily for 12 weeks and overweight individuals, or obese individuals was found to increase BDNF and improve mood in the last one is L theanine, Elfine. And we’ve talked about before on the podcast green tea is how I get a good dose of L theanine. But you know, I also make sure I get good protein intake. But Elfine is antioxidant is neuroprotective. It’s mood enhancing, it has analytic effects, it supports the immune system, 400 milligrams of L theanine for eight weeks, and they took that every day increase BDNF and patients with schizophrenia. Alright, so this was a pretty technical episode. But we’ve talked about before, I’m not going to dumb things down. I really believe that knowledge is imperative to health, you have to have an understanding of how the system work, the inputs, the outputs. And so we talked a lot about brain derived neurotrophic factor, which is a key molecule for brain health. So if you’re looking to improve your brain health, we’ve given you things that regulate it, how its regulated, things that decrease it, and how you can increase BDNF to overall improve your brain health. Okay, thanks for listening to this episode of The strive for great health podcast. Y’all have a blessed day.

Dr. Richard Harris MD  32:44

Thank you for listening in to strive for great health podcast with your host Dr. Richard Harris. It’s our mission and goal at the podcast to impact as many lives as possible to empower individuals to take control of their health and live a life full of joy and purpose. You may help us achieve this mission by leaving a five star rating and review on your preferred podcast platform. And by sharing this podcast with anyone you think it may help. You can also support the podcast by making a donation to your favorite charity. If you do so and send us an email. We’ll give you a shout out on the podcast because here’s the Stratfor great health podcast. We’re all about charitable giving and making the world a better place. Thank you for listening and God bless

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