A (12:36)

Helping me carry my Christmas tree. Zoe. This thing weighs a ton. Drew Ski lift with your legs man.

B (12:41)

Santa. Santa, did you get my letter?

A (12:43)

He's talking to you, Bridges.

B (12:44)

I'm not. Of course he did.

A (12:46)

Right Santa, you know my elf Drew. He handles the nice list. And elf, I'm six' three. What everyone wants is iPhone 17 and at T Mobile. You can get it on them. That center stage front camera is amazing for group selfies, right? Mrs. Claus? I'm Mrs. Claus's much younger sister and AT T Mobile there's no trade in needed when you switch, so you can keep your old phone or give it as a gift. And the best part? You can make the switch to T Mobile from your phone in just 15 minutes. Guys, my side of the tree is slipping. Jim Burr the holidays are better. AT T Mobile switch in just 15 minutes and get iPhone 17 on us with no trade in needed. And now T Mobile is available in US cellular stores with 24 monthly bill credits for well qualified customers plus tax and $35 vice connection charge credits and balance 2 if you pay off earlier, cancel finance 256 gigs $830 eligible for in a new line $100 plus a month plan without our payments, taxes and fees required. Check out 15 minutes or less per line. Visit t mobile.com.

B (13:38)

Now. How do ketones reduce the afterload? This brings us to their direct effects on blood vessels. Work from the University of Aras and other labs has demonstrated that BHB acts directly on vascular smooth muscle and endothelial cells to cause vasorelaxation. So if you're looking down the length of a blood vessel, you have the endothelial cells lining the innermost part and then the smooth muscle which can contract or constrict or relax is outside of that. And again, BHB affects both in preclinical studies at very physiological levels of ketones. So in the 2 to 4 millimolar range, that's higher but very achievable just through normal long term fasting or of course through exogenous ketones. But they found that BHB increased arterial diameter by 30 by about 32%. And of course, the bigger that gets, the lower the vascular resistance is. If it's. If it's a bigger tube than the liquid, in this case the blood, the fluid can move through it much more easily. The mechanism that explains that relaxation, or the expansion of the arteries appears to involve both ion channels, specifically potassium, as I'll note, as well as a production of nitric oxide. Changes in potassium levels will alter the ability of the smooth muscle to relax. It actually just changes the polarization or how inclined the muscle would be to contract. And of course, the increased nitric oxide is then having an effect, albeit much more modestly, like a medication like Cialis. Some of these drugs that are taken in order to induce vasodilation, BHB has a similar effect, again, albeit more modestly. In a 2023 review paper recently published in Nature Cardiovascular Research, the authors emphasize that the vascular effects extend even to the endothelial cell. So everything I just got done describing is a mechanism whereby BHB affects the muscle surrounding the endothelial cells. But there's evidence to show that it also affects the endothelium itself in heart failure. So when the heart is suffering, there's a phenomenon called microvascular rarefication. In other words, the small blood vessels are getting increasingly rare, or you're losing them naturally. That is going to impair the degree to which blood can perfuse through the heart muscle itself. Remember, heart has a very high metabolic demand. With that high demand comes a high requirement for blood flow. So the heart needs to be able to pump blood into its own muscle tissue. But with heart failure, those small, little blood vessels are starting to go away. Well, ketone oxidation in endothelial cells appear to enhance endothelial cell proliferation, which can then act to prevent this blood vessel loss, thereby maintaining that microvascular network that is so important for the very busy and very hungry myocardium, or heart muscle, to continue to function. Now we need to shift from thinking about ketones purely as metabolic substrates to understanding them more as signaling molecules. And this is where things get even another layer of fascinating science. BHB functions as an endogenous histone deacetylase inhibitor, particularly targeting Class 1 HDACs. HDACs. By inhibiting these enzymes, BHB can actually promote histone hyperacetylation. This has a phenomenon within the cell of opening up the chromatin structure and thereby enhancing the transcription of specific genes along chromosomes or along DNA. And among these genes that are now able to be transcribed more readily, we get more of it we have some that encode for antioxidant proteins like FoxO3a or metallothione 2 or thioedoxin, a very important one. The practical implication of this is enhanced resistance to oxidative stress. The heart, with its very massive oxygen consumption is particularly vulnerable to oxidative damage by promoting antioxidant gene expression. Ketones provide a form of molecular armor or just a better defense. But it doesn't end there. Perhaps even more fascinating is the discovery that beta hydroxybutyrate can directly modify proteins through a process called lysine beta hydroxybutylation. This is once again a histone modification similar to what I just mentioned with acetylation or even methylation. If you've heard of DNA methylation. And in this case it appears that with the beta hydroxybutylation we activate transcription of genes in starvation response, metabolic pathways or those that are activated with autophagy in the heart. This post translational modification may regulate gene networks involved in metabolism, stress response and just adaptation to cellular stress. But it's another layer of how ketones communicate information to cells simply, well beyond simply just being burned for energy. Now, the signaling effects do not stop even there. One of the most important signaling effects of BHB relates to inflammation. A seminal paper published 10 years ago 2015 demonstrated that BHB specifically inhibits the NLRP3 inflammasome, something you've probably heard me discuss abundantly. The NLRP3 inflammasome is a molecular complex that when activated triggers not only proteins involved in apoptosis or cell death, but also the release of many pro inflammatory cytokines. This inflammasome is implicated in numerous cardiovascular pathologies including heart failure and atherosclerosis and cardiomyopathy. But this team in the 2015 paper found that BHB suppressed the NLRP3 inflammasome in response myriad pro inflammatory stimuli. So even when you tried to induce inflammation, if BHB is up, it keeps things turned down. And this was a specific effect to bhb. Other ketones like acetoacetate or acetone did not have this effect. For the heart. This is very clinically meaningful because part of heart failure with NLRP3 activation is this inflammation driven cardiac remodeling. So the actual substance of the heart muscle itself becomes kind of broken or compromised because of the inflammation. By inhibiting this pathway, ketones now have an entirely new way of protecting the heart. Because if you can tamp down the inflammation, you increase the potential of the heart maintaining its normal structure. And a lot of what I've said actually connects back to SGLT2 inhibitors. Now again, SGLT2 inhibitors were first used for their antidiabetic effects. You're forcing the glucose out of the kidneys which helps blood glucose levels come down. But an off target effect is the stimulation of ketone production. And indeed people who take SGLT2 inhibitors will consistently have higher levels of ketones. You are just driving or activating greater ketogenesis. Multiple studies have demonstrated that these drugs, SGLT2 inhibitors, blunt the NLRP3 inflammasome from activating which could be through the ketone mechanism. So even these anti inflammatory effects of the SGLT2 inhibitors could be a result of the increased BHB. Now a topic that I've alluded to throughout this mini lecture has been the oxidative stress. Now I mentioned a moment ago that BHB upregulates antioxidant gene expression like genes like Foxo3a which then encode proteins that help neutralize oxidative stress molecules. But second, ketone oxidation itself appears to produce fewer reactive oxygen species than when other fuels are metabolized. For example, the most common fuel, fatty acids. When fatty acids undergo beta oxidation, they can generate significantly more oxidative stress byproducts than ketones are. So when ketones are being used for fuel, as I alluded to earlier, they're producing more ATP with less oxidative stress produced. But third, studies have shown that BHB can directly upregulate thioredoxin 1, a key antioxidant protein in heart muscle cells. So this provides another level of protection.

A (22:51)

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B (24:24)

Now I'd mentioned this one and let's revisit the idea of cardiac remodeling. This is the process by which the heart changes its size, shape and function in response to injury or hemodynamic stress like chronic hypertension. But it is a hallmark of heart failure progression, while ketones appear to beneficially modulate this process. One study model here is something called the canine pacing model of heart failure. And I mentioned earlier, a study that shook found that chronic BHB infusion completely prevented rises in left ventricular and diastolic pressure and it preserved heart rate. And this was a study I alluded to, although I didn't give this level of detail. But it also reduced the pacing induced diminution of cardiac output in ejection fraction. All of this to say simply that every measured marker of heart failure was improved with bhb. And it also the BHB helped the left ventricle, which is the main ventricle of the heart that does all the work. When you think of the heart pumping blood out, it helped prevent this. Not only it restored the ability to dilate or expand, but it also prevented the heart muscle from getting too thick. That's something called cardiac hypertrophy. So one of the versions of heart failure is when the heart muscle is getting thicker and thicker and making the chamber get smaller and smaller where it can't hold as much blood. BHB prevented all of this in heart failure with compromised ejection fraction. BHB just kept everything working totally normal. Again, a pretty remarkable finding. Now, with all of these mechanisms and energetics in mind, how can we translate some of this into practice? I think there are several approaches worth investigating. So firstly, ketogenic diets studies have shown that ketogenic diets can reverse some of the compromised enzymes involved in energy, like succinate dehydrogenase activity in cardiomyocytes. However, the effects are nuanced and prolonged ketogenic diets may may have other off target Effects that someone doesn't want, like for example, increased uric acid. Although again, if the problem with uric acid is inflammation, BHB reduces that inflammation. A paper my lab published. But with exogenous ketones, we have another opportunity where if someone is interested in bumping up ketones without perhaps the rigor of a ketogenic diet, then you have a very viable way of doing that. In heavy or hearty defense of exogenous ketones. One of the most powerful studies I mentioned was one that used lbhb. If you're interested in lbhb, you've really got to focus on exogenous ketones. Your own production of LBHB is very modest. The human body does not make a lot. Now, that does not mean it's irrelevant, because as one of the studies I alluded to showing profound improvements in cardiac output, only saw that that was happening with L BH B. To wrap up, let me synthesize what we've covered. Ketones, most especially bhb, serve the heart in multifaceted ways that extend far beyond simple fuel provision. As an alternative fuel, I wouldn't say backup. They provide ATP when fatty acid and glucose oxidation are impaired in the failing heart, with better oxygen efficiency, so producing more ATP per unit oxygen, oxygen consumed. Beyond that, as hemodynamic modulators, they reduce afterload through direct vasodilation, making the heart's job easier and increasing cardiac output without increasing the strain of the heart. As anti inflammatory agents, they specifically inhibit the inflammasome, reducing inflammation that can drive adverse cardiac remodeling, not to mention atherosclerosis. As antioxidant promoters, they upregulate myriad antioxidant genes, which just helps control or reduce oxidative stress. And then there are further effects as you have BHB acting as a signaling molecule and even helping reduce the loss of the small blood vessels that feed through the myocardium. So when it comes to the heart, in my view, the evidence is unambiguous. Ketones are cardiovascular allies that extend far beyond their role as just a fuel, which is how they're so commonly viewed. They represent what we might call a metabolic signal of fasting, a signal that paradoxically can improve cardiovascular resilience. The fact that the failing heart actively upregulates its ketone oxidation machinery tells us something important about the adaptive value of these molecules. In fact, I cannot help but be struck by how analogous that is to the failing brain, that when the brain is experiencing its decline in function, it also starts increasing its reliance on ketones as a fuel. Unfortunately, you utter the word ketone around many people, even those who should know better, and it just erodes into an ideological debate about macronutrients, which can really just obscure a lot of these findings. People's general wariness of ketones, I would say born primarily from ignorance, causes them to just be totally unaware of or force them to overlook many of the benefits from these very well conducted studies that I've outlined. As an aside, if you're interested in trying exogenous ketones, I strongly recommend cleanformnutrition.com that's where I go to get mine. In fact, so much so that they've given me a discount code that I can share. Use the code BEN10 for 10% off. Class dismissed. Until next time. More knowledge, Better Health. Think enterprise software is too costly, too complex and takes too long to get up and running? Think again. Workday Go makes simplifying your small or mid sized business simple HR and finance together on one powerful AI platform right at your fingertips. Workday Go gets you live fast and fits the needs of your business. Find out what Workday Go can do for you. Go with Workday Go.

A (31:14)

This holiday season, Capital One reminds you to give yourself the gift of 1.5% cash back with the Capital One Quicksilver Card. Can I earn 1.5% cash back on birds? Birds? What if you sent your true love two turtle doves plus a partridge and a pear tree? Sure, but why would anyone want that? The song was very convincing. Earn 1.5% cash back on all your holiday purchases with the Capital One Quicksilver Card. What's in your wallet? Terms apply. See capitalone.com for details.

B (31:45)

Mic check 1 to Are we recording? Hi, I'm Michelle Bernstein, an award winning chef, restaurateur and mom. I have a lot on my plate, including my psoriatic arthritis symptoms. That's why I was prescribed Cosentyx. It helps me move better.

A (32:03)

Cosentyx Secukenumab is prescribed for people 2 years of age and older with active psoriatic arthritis. Don't use if you're allergic to Cosentyx. Before starting, get checked for tuberculosis. An increased risk of infections and lowered ability to fight them may occur like tuberculosis or other serious bacterial, fungal or viral infections.

B (32:20)

Some were fatal.

A (32:21)

Tell your doctor if you have an infection or symptoms like fevers, sweats, chills, muscle aches or cough, had a vaccine or planned to, or if inflammatory bowel disease symptoms develop or worsen serious allergic reactions and severe eczema like skin reactions may occur. Learn more at 1-844-COSENTIX or Cosentix.

B (32:40)

Ask your rheumatologist about Cosentix.