Ep 217 The High Stakes of Cholesterol

So your latest blood test results have come in, and you see a couple of numbers for cholesterol. What do those numbers mean, and why do we care about them? In this first part of our cholesterol miniseries, we break down the science behind this compound and trace how we made the link between certain types of cholesterol and heart disease. First, we follow the path that cholesterol takes in our bodies and what LDL and HDL mean in the context of heart disease. Then we delve into the history of this compound, which involves an over 2 billion year journey back in time, fascinating experiments that revealed the stubborn nature of medicine, and a terrible - but hopefully memorable - baseball analogy. Tune in for the low down on cholesterol. Support this podcast by shopping our latest sponsor deals and promotions at this link: https://bit.ly/3WwtIAu See omnystudio.com/listener https://omnystudio.com/listener for privacy information.

• 0:01Speaker 00

  This is exactly right.

• 0:06Speaker 01

  Breathe in and reset with Lincoln Rejuvenate, an available multisensory feature in the 2027 Lincoln Navigator SUV. Experience the luxurious massage, visuals, and sense to help you relax in the driver's seat. It's your time for a reset. Visit Lincoln.com to learn more. Lincoln Rejuvenate does not operate unless the vehicle is in park, when the vehicle is off, or if any doors open. Do not use the feature in a closed garage or in other enclosed areas. See owner's manual for important operating instructions. Lincoln and Navigator are trademarks of Ford or its affiliates. All rights reserved.

• 0:37Speaker 02

  CBS Thursday, there's something different about our new CBS Family Comedy, Eternally Yours.

• 0:43Speaker 03

  Are you all vampires? Is that why none of you age?

• 0:45Speaker 02

  From the mortals who brought us the hit comedy Ghosts.

• 0:48Speaker 04

  I don't want you dating a human. You are being so unfair. Well, life is tough and then you continue to not die.

• 0:54Speaker 02

  A new family comedy with bite.

• 0:55Speaker 05

  You have to formally invite me in.

• 0:57Speaker 02

  Oh, this is what you think? Don't worry, I will. Are you any garlic? That's actually a very offensive stereotype. The new comedy, Eternally Yours, new CBS Thursday, 8:30, 7:30 Central.

• 1:06Speaker 06

  This is Danielle Fishel from Pod Meets World. When my skin is feeling dry, I want a moisturizer that I can actually feel working. But I don't want to feel it sitting on my face all day. That's what I love about Clinique Moisture Surge 100 Hour Moisturizer. It's this lightweight gel cream that absorbs so quickly and my skin just feels instantly refreshed, plump, and hydrated. Never greasy or heavy. And somehow that hydration lasts for up to 100 hours. It's oil-free, fragrance-free, allergy-tested, and safe for sensitive skin. Try Clinique Moisture Surge 100 Hour today at Clinique.com. Feels like Moisture Surge.

• 1:45Speaker 07

  The firsthand account for this episode features a story involving the death of a family member. Some listeners might find this upsetting, so please listen with discretion.

• 1:56Speaker 08

  Hi, I'm Tori and I have familial hypocholesterolemia. I think growing up, I always knew my dad was different because he like walked with a limp and he spoke weirdly. He couldn't like write or do anything, but I didn't know why. And then I remember when I was 10 years old, my mom requesting that I get my cholesterol checked at a doctor's appointment and they're like, she's 10. I think it was when they sat me down and told me that my dad had had a heart attack, which turned into a stroke when I was a baby. And so that's why things were a little different. And then that the same thing happened to

• 2:36Speaker 08

  his father. His father was 45. My dad was 47 when he had his heart attack. And then they told me what causes it and why they're worried that I could have it. When I was 14, my cholesterol was 232, which not good. And they told me like, oh, diet and exercise, come back in a year. And it was 231. And so we were like, this is something more. It's not just lifestyle. But then the pandemic happened and there was like so much going on, but I finally got like tested again and they were like, we can't put you on statin unless you have

• 3:21Speaker 08

  a geneticist prove that this is something. So I had to go to a geneticist and I have a fun little chart that's like, she's missing something. That's now what I live with. I'm on statin for the past two years. My cholesterol is 197, still a little high. But last July, I was taking a nap and I got like shook awake by my brother-in-law. And I hear like sobbing in the background and I remember being told, we have to go to the hospital right now. And I checked my phone and there's a text from my mom that says, your sister's heart stopped and the name of the hospital that they were at.

• 4:03Speaker 08

  And so we speed over there and when we get there, the chaplain tells us that there was nothing they could do. She was only three weeks away from her 26th birthday. It was kind of a huge shock and kind of be like, oh, this is real. This is like real, real, you know? So yeah, that's something that I live with and the constant back of my mind. I don't really know how to talk about it unless it's like, fun fact, my DNA is missing, you know? But it always comes up where I'm like, oh, I don't eat red meat. Oh, I can't have that.

• 4:46Speaker 08

  I can't do this. I have to take my pills. I have a plethora of pills that I take every morning and night. For a bit, my twin had to wear a heart monitor because they now have Afib. I bedazzled it for them. It is something that's discussed openly. I think that fear has gotten really largely into my mom's head. And she's like, you have to take this, this, and this. And are you doing like your exercises? And stuff like that. And so I think it is just very established that this is a fear. It's a huge part of my life and then it's a huge part of my anxiety. Where it's like, this could be it. But I think just realizing that this is going to

• 5:30Speaker 08

  be the rest of my life and it may not be as long as, you know, others. And my dad was lucky to survive his heart attack. His father and my sister were not. So it's just kind of this like constant worry that this might happen and a lot sooner than you'd think.

• 6:37Speaker 07

  Tori, thank you so much for taking the time to chat with us and share your story. We deeply, deeply appreciate it.

• 6:45Speaker 08

  We do. Thank you so much.

• 6:48Speaker 07

  Hi, I'm Erin Welsh.

• 6:49Speaker 06

  And I'm Erin Allman Updike.

• 6:51Speaker 07

  And this is This Podcast Will Kill You.

• 6:53Speaker 06

  And today we're talking about cholesterol.

• 6:56Speaker 07

  Today and next week.

• 6:58Speaker 06

  Today and next week. Because it's kind of a big deal, so it's going to take a while.

• 7:02Speaker 07

  A pretty big deal. It's a pretty big deal. Yeah, we decided to divide this up into two different episodes because the first is really about cholesterol because, you know, LDL is one, just one part of the cholesterol story. Atherosclerosis is just one part of the story. And so that's the story that we're going to be talking about this week. So the role of cholesterol in our bodies overall and the role of cholesterol in disease.

• 7:26Speaker 06

  Yeah.

• 7:27Speaker 07

  And then next week, we're talking statins.

• 7:30Speaker 06

  We're talking, what do we do about it?

• 7:32Speaker 07

  What do we do about it? It won't, it won't just be statins, but it will be focused on like, how do we lower cholesterol and why would we lower cholesterol?

• 7:41Speaker 06

  And why?

• 7:41Speaker 07

  Yeah.

• 7:42Speaker 06

  And how low can we go? Just kidding. That is like a very small part, but.

• 7:45Speaker 07

  Yeah. I was gonna say, there is a low that is too low, correct?

• 7:49Speaker 06

  Yeah. Yes.

• 7:50Speaker 07

  Yeah.

• 7:50Speaker 06

  We do need it.

• 7:51Speaker 07

  There's, there's a lot of good material to cover, so let's just get through the rest of this intro.

• 7:59Speaker 06

  Let's do our necessary things.

• 8:00Speaker 07

  To say that it's not exciting, but like, you know, we want to get to the meat of it. It's quarantine-y time. Disaster. What are we drinking this week?

• 8:09Speaker 06

  We're drinking Plaque Attack.

• 8:11Speaker 07

  Plaque Attack.

• 8:11Speaker 06

  Plaque Attack. Are we attacking Plaque? Is Plaque attacking us? A little bit of both.

• 8:17Speaker 07

  Yeah. Plaque Attack is a delicious bev. It has blueberries and lemon juice and sparkling water and a little bit of simple syrup and some mint to make it nice and refresh.

• 8:30Speaker 06

  Yeah. Has nothing to do with your cholesterol, but it is delicious.

• 8:34Speaker 07

  Yeah.

• 8:34Speaker 06

  We'll post the full recipe on our website, thispodcastwillkillyou.com, and all of our social media channels too. So are you following us there? Because then you could see this.

• 8:43Speaker 07

  You could see this. You could see this. You also could see this if you go to our website, thispodcastwillkillyou.com, which features not just pictures of quarantine-y recipes and still maybe videos from past ones working on that still, still. And, but you can also find things like transcripts. You can find our show notes. You can find links to bookshop.org affiliate page, music by Bloodmobile, about us page, merch, Patreon. Submit your firsthand account form, contact us form. I got there in the end.

• 9:18Speaker 06

  You did. You really nailed it, Erin. I don't think you missed a single thing.

• 9:22Speaker 07

  Thanks for saying that.

• 9:25Speaker 05

  Uh, that's all we got, right? We can just-

• 9:27Speaker 07

  Yeah, I think so. Rate, review, subscribe.

• 9:31Speaker 05

  Do those things.

• 9:32Speaker 07

  Um, and also, I'll just throw it out there. You know, thank you to everyone who has ever suggested an episode topic. It's really helpful. We love getting topic ideas from you all and feedback from you all. And so, keep it up.

• 9:45Speaker 05

  Yeah.

• 9:45Speaker 07

  We love it.

• 9:46Speaker 05

  Also, thank you to everyone who has submitted firsthand accounts. We-

• 9:49Speaker 07

  Yeah, too.

• 9:50Speaker 05

  We really do read them all. And sometimes it might take us like, I don't know, two or three years to reach out to you.

• 9:56Speaker 07

  It may.

• 9:56Speaker 05

  But that doesn't mean that-

• 9:57Speaker 07

  Even longer at times. I'm wondering what our record is.

• 10:00Speaker 05

  Yeah. More than three years. But thank you. We really do appreciate it. And like, being able to hear all of your stories and share your stories, it's what makes this podcast, in our opinion. So, thank you.

• 10:12Speaker 07

  Absolutely. Well, let's take a quick break and then get into the story of cholesterol.

• 10:18Speaker 05

  Let's.

• 10:21Speaker 09

  When intimate itch strikes, waiting it out isn't always an option. That's why there's Vagisil Maximum Strength Anti-Ich Cream. It provides fast relief from intense external feminine itching and burning. And 92% of women said Vagisil provided long-lasting itch relief. Intimate itch can have more than 60 causes. From everyday things like shaving, pads, tight clothing, to yeast-infection-related irritation. Vagisil helps protect delicate skin from further irritation. Trusted by generations, clinically and gynecologist-tested. Don't let discomfort get in the way. Visit vagisil.com to find the relief that's right for you.

• 10:52Speaker 07

  Fall is a great season for looking like you tried harder than you did. Put on a good sweater, throw on some nice jeans, and suddenly you're an upstanding member of society. For clothes that do some of the work for you, there's Quince. Quince specializes in effortless, high-quality essentials like ultra-soft organic cotton and premium Mongolian cashmere sweaters. They're beautifully tailored, built to last, and transition seamlessly from morning meetings to dinner. And as the weather gets colder, Quince has everything you need to round out your wardrobe. From warm, responsibly sourced down jackets and cozy cashmere scarves and gloves, to beautiful 14-karat gold jewelry that adds the perfect finishing touch. Everything at Quince is priced 50 to 80% less than similar brands.

• 11:35Speaker 07

  They work directly with ethical factories and cut out the middlemen. So, you're paying for quality, not brand markup. My fall wardrobe has basically become my Quince Bella Stretch Wide-Leg Jeans with my 100% organic cotton-cropped polo sweater. Comfy and flattering, it's the best. Find the fall pieces you'll reach for most at Quince. Download the Quince app for app-exclusive offers or go to quince.com. Get free shipping on your order and 365-day returns. Now available in Canada and the UK, too. And when Quince asks where you heard about them, let them know it was this podcast will kill you. It's the best way to support the show.

• 12:11Speaker 10

  Lisa, we should tell them about our new show. Oh, my God, Lexi, we have a new podcast. It's called Don't Lie to Me. I'm Lexi Iwanu. We're two best friends, 22 years apart, but so close at heart.

• 12:24Speaker 03

  And I'm Lisi DiGiulio, the old one, which means we have wildly different references, occasionally different opinions. And at this point in my 50s, I've lived it all.

• 12:33Speaker 11

  I'm not gonna get anywhere fighting. That is wild. I learned that about you today.

• 12:40Speaker 10

  Now in my 30s, being the founder of New Shoes, good taste is my business. And I've always got something to say. If men were just honest about this, there would be so much more peace in the world.

• 12:51Speaker 03

  We're gonna talk about dating, relationships, beauty, getting older- And a little wiser. We're best friends, but we don't always agree.

• 12:58Speaker 12

  Because you told us how accommodating you are. Obviously, I would do what I think I could do to fight the fight, but there's only so much fight I can fight.

• 13:06Speaker 10

  Don't lie to me. Don't lie to me. Don't lie to me. Don't lie to me. Don't lie to me. Don't lie to me. Liar. Listen on the iHeartRadio app, Apple Podcasts, or wherever you get your podcasts. I don't really care.

• 13:34Speaker 05

  My goal for you today is that in the next, I don't know, 20 minutes or so-

• 13:40Speaker 07

  Okay.

• 13:40Speaker 05

  You will understand what on earth cholesterol actually is and what our bodies are supposed to be using it for. And then, what your doctor actually means when they talk about your quote-unquote "cholesterol" and why those levels matter for your health. All right?

• 13:58Speaker 07

  Love this.

• 13:59Speaker 05

  Okay. So, cholesterol itself is a type of lipid molecule. And we think of lipids as fats. Technically, fats are just triglycerides, but whatever. Think of them as fats. And it's specifically a type of lipid called a sterol, like cole-sterol. Okay? Cholesterol is just a string of carbons and hydrogens and one oxygen that's formed in these little rings. There's like four rings together. So, it's a pretty rigid molecule. And cholesterol is an essential molecule for all animal life. And really, nearly all kinds of life on earth need things like cholesterol.

• 14:43Speaker 05

  So, plants, they don't make cholesterol, really, but they do make a whole bunch of other very similar compounds called phytosterols. Phytosterols. Phytosterols? Anyways.

• 14:56Speaker 07

  I'll accept both.

• 14:57Speaker 05

  Thank you. And fungi make their cell membranes out of something called ergostero. Okay? Sterol, also. And one of the biggest things that sterols, like cholesterol for us animals, does is provide shape and structure to our cell membranes. So, cholesterol molecules are interspersed throughout all of our cell membranes, like the outside of our cells, which is called our plasma membrane. And then also, all of our organelles inside of our cells also have membranes that also have cholesterol within them. And what this does is provide just the right amount of rigidity and structure without being like too solid. Okay?

• 15:37Speaker 07

  Right.

• 15:38Speaker 05

  Cholesterol molecules are also moved back and forth across these cell membranes. They interact with proteins, both inside and outside membranes, and they serve as signaling molecules that helps our cells communicate, like, within the cells, like between organelles, and then also between cells themselves. It's kind of a big deal.

• 15:58Speaker 07

  Cholesterol does a lot of things.

• 15:59Speaker 05

  It really does, because I'm not even done.

• 16:01Speaker 07

  Not even done.

• 16:01Speaker 05

  The backbone of cholesterol, those ring structures of carbons and hydrogens, are also the precursors to all of our steroid hormones.

• 16:11Speaker 07

  Yes, they are.

• 16:12Speaker 05

  So, that's estrogen, testosterone, cortisol, all of them, and vitamin D, and our bile acids, which we learned in our Gall Bladder episodes, pretty frickin' important. So, suffice to say, we need cholesterol in order to be alive. Right?

• 16:30Speaker 07

  Totally.

• 16:31Speaker 05

  Where do we get it from? Let me tell you. We make our own cholesterol. And most all of our cells can make cholesterol, like, all of our cells are capable of it. But it's a pretty energy-intensive process. So, the vast majority of cholesterol that we actually use in our body is made in our liver. And then we also get cholesterol and other fats and fatty acids that we also need from our diet. So, we absorb it through our intestine, and then that gets transported to our liver. So, while our cells can make their own cholesterol, they're generally not making quite enough of it, which is why our liver makes so much, something like more than 50% of the cholesterol that our cells use,

• 17:14Speaker 05

  which means that we have to be able to deliver cholesterol from our liver and our intestine to everywhere else in our body.

• 17:24Speaker 07

  Yeah.

• 17:25Speaker 05

  And our body uses blood to transport stuff around. Okay?

• 17:29Speaker 07

  It's the superhighways of the body.

• 17:32Speaker 05

  Exactly. And so, while cholesterol is integral to life, when it ends up causing problems, which is obviously what we're gonna focus on for this episode, is when that cholesterol starts building up in high amounts in places that it shouldn't. That is where we can end up seeing cholesterol cause disease. And so, to understand how that happens, we have to understand how it is that our body is moving cholesterol around, from our liver to our cells, et cetera, and how our cells are cycling that cholesterol. Because then we can understand how this might build up in places that it shouldn't. Now, lipids, a key thing to understand about them, including cholesterol and all of our other fatty acids,

• 18:16Speaker 05

  is that they are not water soluble. Right? Everyone who's tried to make salad dressing knows this. And what that means is that in order to move cholesterol around our bloodstream, it's not just gonna be free-floating, because it won't do that well.

• 18:34Speaker 07

  Yeah.

• 18:34Speaker 05

  So, we actually move our cholesterol around our body in little packages called lipoproteins.

• 18:43Speaker 07

  Okay.

• 18:43Speaker 05

  Now, we have a bunch of different kinds of lipoproteins, lipofatproteinprotein, and they all serve different functions.

• 18:52Speaker 05

  Most of our cholesterol is made in our liver, right? So our liver takes the cholesterol that it makes, along with other fatty acids and connects it to a protein and sends it out in a box that we call VLDL, or very low-density lipoprotein, right? So it sends that package out, and that is the type of cholesterol package that our cells are going to end up using. Along the way in our bloodstream, this VLDL gets broken down a bit and eventually becomes a smaller box of cholesterol and other fats that we call LDL, or low-density lipoprotein.

• 19:38Speaker 07

  Right.

• 19:38Speaker 05

  Okay. So VLDL and LDL, these are the lipoproteins. These are the packages of cholesterol that our cells are taking up and using for cholesterol.

• 19:51Speaker 07

  Okay, so these are the things that our liver is making to say, here you go. Here's, you said you needed some cholesterol to make your cell membranes or make some hormones or whatever. Here's this package. Starts out VLDL, turns into LDL. Our cells take that up.

• 20:07Speaker 05

  Our cells are like, awesome, I got this. They grab onto it, they bring it inside of them, protein, cholesterol, fatty acids and all, in a little package, right?

• 20:16Speaker 07

  Right.

• 20:17Speaker 05

  Now, once it's in our cells, our cells can either use it or they can store it for later if they're like, I want to have a little extra. Or they might get way too much of it, and then they have to send it back out into our bloodstream. When our cells are going to export extra cholesterol, they do it in a package called HDL, or high-density lipoprotein.

• 20:42Speaker 07

  Okay.

• 20:42Speaker 05

  And that is the cholesterol that's being transported from our cells back to our liver so that our liver can recycle it or excrete it into bile acids or whatever our liver's going to do with it.

• 20:55Speaker 07

  That makes sense. So this is LDL being the, you know, quote-unquote, "bad" cholesterol.

• 21:00Speaker 05

  Quote-unquote "bad", because this is what's going from our liver out to our cells, floating around in our bloodstream, and it's small and it is sticky. So it can get stuck in places in our bloodstream. But it's also what our cells need to take it up and use it. And then HDL is what's going from our cells back to our liver to be recycled.

• 21:23Speaker 07

  Okay, what's the relationship between, or maybe this is jumping ahead.

• 21:28Speaker 05

  Give it to me.

• 21:29Speaker 07

  The relationship between VLDL and LDL, what decides how much your liver is making? If high LDL is the problem, how does that, what's that feedback cycle like?

• 21:41Speaker 05

  Oh, this is a really, really good question, Erin. The balance between how much of the different types of cholesterol packages that we have, VLDL, LDL, HDL, whatever it is, it depends on a lot of different things. It depends on how much your liver is making, and some of that is just genetic. Some of that might have to do with your dietary factors. We know that like diets that are high in fat, especially saturated fat, increase the total amount of all these types of cholesterol in your bloodstream, all these different cholesterol packages. We don't know why, though. It also is going to depend on how good your cells are at taking this cholesterol out of your bloodstream.

• 22:26Speaker 05

  And one of the main things that determines that is how many what are called LDL receptors you have on your cells. These are like Velcro mitts that grab on to those LDL packages of cholesterol really efficiently and pull them into the cells so that those cells can use them. But if you don't have as many LDL receptors or your LDL receptors are not as functional as someone else's, or they just get saturated because you end up with so much of that LDL cholesterol package floating around that all your receptors are full, then you're going to have more of that LDL cholesterol in your body. And what determines how much HDL cholesterol you have

• 23:12Speaker 05

  is even more unknown, because there's definitely like a big genetic factor there, but we don't know, like, why is it that some people's cells are exporting more HDL and others aren't?

• 23:22Speaker 07

  And the VLDL, LDL is just sort of like, that's just a natural progression?

• 23:26Speaker 05

  It's a progression, yeah. And again, it is going to vary person to person, like how quickly that VLDL breaks down into LDL within your bloodstream while it's like bumping around. But it's all very like person-dependent. There's not like a lot of specific...

• 23:44Speaker 07

  It's so tricky, because yeah, there are so many different drivers of LDL.

• 23:51Speaker 05

  Right.

• 23:51Speaker 07

  Like, why, why? Okay, this is getting in a little bit to the evolution question of this, but like, why would it be more beneficial to have more LDL receptors or fewer receptors? Why would it be better to store cholesterol rather than utilize it?

• 24:09Speaker 05

  Such great questions. I don't have answers.

• 24:16Speaker 07

  I had a feeling you were going to say it.

• 24:17Speaker 05

  You know, I never do. But no, those are, those are all really good questions, because that is really the determinant of whether cholesterol is going to become a problem.

• 24:27Speaker 07

  Yeah.

• 24:27Speaker 05

  Is if it is building up in the wrong places or at the wrong times. And there are actually a whole bunch of diseases that I'm not going to get into any detail on today that are where cholesterol is building up, not outside of our cells, not in our bloodstream, but actually inside of our cells. So you can get buildup of fats and cholesterol after that cholesterol has been taken up into our cells if you can't export it, right? So for example, there's a genetic disorder called Niemann-Pick disease.

• 25:03Speaker 07

  Okay, yeah.

• 25:04Speaker 05

  And this is where you have a defective, basically exporter molecule.

• 25:08Speaker 07

  And so you would, you would have really low HDL levels.

• 25:11Speaker 05

  Low HDL levels and just low cholesterol levels overall, because you're still taking up cholesterol

• 25:16Speaker 07

  Taking it up, yeah.

• 25:17Speaker 05

  From your bloodstream, but then you can't get rid of it. And now your cells are too full of cholesterol, right? So that's going to be really detrimental. There are other ones as well, and I'm not going to get into deep detail, because the way that we tend to worry about the buildup of cholesterol for most people is when it builds up in our bloodstream, because that is when we see increased risk of a number of different diseases, but especially atherosclerosis, which is the fancy name for when cholesterol builds up in your blood vessels.

• 25:53Speaker 07

  Okay, so cholesterol meaning these packages, these LDL packages specifically?

• 26:00Speaker 05

  Well, yes, so here's what happens. When you have high levels of these LDL packages, or not just LDL packages, but other, like VLDL, like other cholesterol packages that are not HDL, okay?

• 26:16Speaker 07

  Okay.

• 26:16Speaker 05

  Non-HDL cholesterol. If that's high levels in your bloodstream, then sometimes, because many of those particles, especially LDL packages, are small and sticky

• 26:30Speaker 07

  Yeah.

• 26:30Speaker 05

  in our blood vessels, especially maybe at, say, bifurcations, like somewhere where your blood vessels split or a curvature or a place where you got damaged for some reason or another, those molecules can get stuck along the walls of our blood vessels, and they get just underneath the first layer of cells into the wall of our blood vessel. And once they are there, those packages kind of disintegrate, and then you do have just free cholesterol molecules in the wall of our blood vessel. And our immune system is like, whoa, dude, you're not supposed to be here. You're only supposed to be inside of cells or attached to your little protein package.

• 27:15Speaker 05

  What the heck are you doing here? So our immune system triggers a huge inflammatory response. And then that cycle basically can kind of continue. More cholesterol gets stuck because there's inflammation in the wall of your blood vessel. That triggers more inflammatory markers to come in. And then over time, you get this buildup of actual free cholesterol, not just these packages, but like cholesterol floating underneath the wall of your blood vessel.

• 27:44Speaker 07

  Okay.

• 27:45Speaker 05

  And then as these plaques build up and our body is trying to respond to it, eventually we build this kind of fibrous cap over it. Our smooth muscle cells build a cap, and eventually they calcify. And that's all our body's response to try and stop this thing that's in the walls of our blood vessels from taking over, essentially.

• 28:08Speaker 07

  Okay, so it's essentially a numbers game in that, you know, we can throw things like the LDL receptors in there, we can throw, but ultimately it comes down to how much LDL is in your bloodstream that is not being taken up by cells for whatever reason. And that just is, is associated with more of these little clogs, these little, it's sort of sticking to the walls of your arteries, and then that cholesterol leaking out into the actual lining, causing inflammation and an immune response, which then leads to hardening and plaques, et cetera, and problems down the line.

• 28:49Speaker 05

  Exactly.

• 28:50Speaker 07

  Or immediately.

• 28:51Speaker 05

  Or immediately, yeah. So those problems could be that the plaque gets so big that it actually blocks the vessel entirely. Or it could be that the plaque gets big and then becomes unstable, and a chunk of it breaks off, travels farther down and blocks smaller arteries.

• 29:09Speaker 07

  Okay.

• 29:10Speaker 05

  Okay.

• 29:12Speaker 05

  That's cholesterol and how it causes atherosclerosis. That's as short as I could make it, Erin.

• 29:19Speaker 07

  Tell me about the relationship between LDL and things like age, things like diet. I know you mentioned saturated fats, but like, and you said, we don't know the mechanism. And then also some hard numbers here, like what levels are we talking about? And what is important to consider? Like, what is that? If you have a high LDL, is that a snapshot in time? How long has it been high?

• 29:50Speaker 05

  Oh, these are really fun questions. So yeah, in general, your total amount of cholesterol. And when we're measuring your total cholesterol, we're measuring all these different types of packages, right? We're measuring the HDL packages. We're measuring the LDL packages. We're measuring all the packages.

• 30:05Speaker 05

  It is going to go up as we get older. Why? I don't know.

• 30:10Speaker 05

  Or is it because our LDL receptors that are taking this up are getting less efficient or not being recycled as easily? I don't have a perfect answer for you, but cholesterol does go up as we get older. So that is one of the biggest risk factors for atherosclerosis in general is just age, and we can't do anything about that.

• 30:33Speaker 05

  You also asked about diet and other things that are going to influence it. Diet can have, and not just diet, also like physical activity levels. And what types of, especially fat, so saturated fat versus unsaturated fat versus dietary cholesterol, versus how many carbohydrates you're getting. All of that is going to affect your body's cholesterol levels and all the different, like ratios of these different packages that we have. And we don't fully understand the exact mechanisms of how this happens. But what we do know is that diets that are higher in saturated fats

• 31:18Speaker 05

  tend to increase both your total amount of cholesterol and specifically your LDL cholesterol levels.

• 31:26Speaker 07

  Okay.

• 31:27Speaker 05

  But not your HDL cholesterol levels.

• 31:30Speaker 07

  Your body maintains a fairly consistent ability to produce HDL. And so HDL is independent of LDL levels.

• 31:41Speaker 05

  Yeah.

• 31:42Speaker 07

  Okay.

• 31:43Speaker 05

  Yeah, they're not directly connected. There are things that you can do that will sort of shift their proportions, right? Increasing physical activity is actually one of those that ends up increasing the amount of HDL and lowering the amount of LDL. But there are lots of other things that might just affect one versus the other. HDL is one of the harder ones because it's just really, we don't fully understand, like, how do we? We know that having higher levels of HDL is protective against heart disease.

• 32:15Speaker 07

  Right.

• 32:16Speaker 05

  But we don't know why exactly. We don't know exactly what levels it's at, and we don't really have a lot to do to try and increase somebody's HDL, for example.

• 32:30Speaker 07

  Okay.

• 32:30Speaker 05

  Isn't that interesting?

• 32:32Speaker 07

  And so, go ahead.

• 32:33Speaker 05

  And you asked about hard numbers.

• 32:35Speaker 07

  Yes, yes, yes, yes.

• 32:36Speaker 05

  Now, these are going to depend a little bit on which guidelines that you're looking at and things like that. But like, right now, the general consensus is that, quote unquote, ideal levels of LDL cholesterol would be less than 100 milligrams per deciliter in your blood.

• 32:54Speaker 07

  Okay.

• 32:55Speaker 05

  Does that mean that if you have more than 100, you're going to have plaque buildup and you're going to have a high risk of heart attack? No, absolutely not. But we know that levels above 100 are associated with higher risk than levels below 100. And we know that it's not quite like a linear relationship, but it is definitely an increasing risk with increasing LDL levels above 100.

• 33:21Speaker 07

  Yes, okay.

• 33:22Speaker 05

  So especially as those levels get to be above 160 or 190 milligrams per deciliter, then we are looking at, that is considered a very high level of LDL in the bloodstream.

• 33:35Speaker 07

  Okay.

• 33:36Speaker 05

  And total cholesterol, again, it's going to vary. Usually under 200 or even under 160 would be considered ideal total cholesterol. And that's going to be, again, a measure of your LDLs, your HDLs, and all the other types of lipoprotein cholesterol packages.

• 33:52Speaker 07

  Okay.

• 33:53Speaker 05

  Okay.

• 33:54Speaker 07

  And so when people talk about lifestyle modifications for managing cholesterol levels, is that mostly geared towards decreasing LDL with the kind of beneficial side effect of also hopefully increasing HDL? If it's something like exercise or certain types of food that have an impact on both?

• 34:12Speaker 05

  That's exactly what it is. Yes. Yeah, it's all about dietary intervention. So decreasing saturated fats, increasing whole grains and plant-based proteins that have higher amounts of unsaturated fats.

• 34:24Speaker 07

  Yeah, yeah.

• 34:24Speaker 05

  And then increasing physical activity.

• 34:27Speaker 07

  Okay.

• 34:28Speaker 05

  Now, atherosclerosis or heart disease, cardiovascular disease, which are not all exactly the same thing, but I'm using them interchangeably.

• 34:38Speaker 05

  That is not the only thing that's associated with high levels of cholesterol or high levels of LDL cholesterol, right? There are a lot of other things that are associated. And even when we hear the term cardiovascular, you might think that's only your heart. And yes, I'm talking about heart attack. I'm talking about heart disease, but I'm also talking about stroke. I'm also talking about chronic kidney disease, peripheral artery disease. And there's a whole range of other diseases that the more that we look for associations between high levels of LDL and other diseases, we find them. Liver disease. There's also strong associations between certain types of lipoproteins and an increased risk of Alzheimer's disease.

• 35:21Speaker 05

  And even though that's only like a strong association with one type of this lipoprotein cholesterol package, it does look like lowering total amounts of LDL cholesterol can also lower the risk of Alzheimer's disease. Right? So there are these other associations. There's some thought that there's associations with cancer, and we just don't know the exact mechanisms of all of this. But high levels of LDL cholesterol are associated with this increased inflammatory response and this buildup of cholesterol, especially in the arteries in your blood vessels.

• 35:58Speaker 05

  So that's cholesterol, Erin. There's a lot more detail that I gotta be done, you know?

• 36:07Speaker 07

  It's a strange, it's a strange beast.

• 36:10Speaker 05

  Yeah, yeah.

• 36:12Speaker 07

  Yeah.

• 36:12Speaker 05

  So can you tell me? You know, I don't even know, I don't even know.

• 36:17Speaker 07

  You don't even know. You know, we'll find somewhere to begin. I think I can, I can make that happen.

• 36:25Speaker 09

  When intimate itch strikes, waiting it out isn't always an option. That's why there's Vagisil Maximum Strength Anti-Ich Cream. It provides fast relief from intense external feminine itching and burning. And 92% of women said Vagisil provided long-lasting itch relief. Intimate itch can have more than 60 causes. From everyday things like shaving, pads, tight clothing, to yeast infection-related irritation, Vagisil helps protect delicate skin from further irritation. Trusted by generations, clinically and gynecologist-tested. Don't let discomfort get in the way. Visit vagisil.com to find the relief that's right for you.

• 36:57Speaker 10

  Lisa, we should tell them about our new show.

• 37:01Speaker 03

  Oh, my God, Lexi, we have a new podcast. It's called Don't Lie to Me.

• 37:05Speaker 10

  I'm Lexi Iwanu. We're two best friends, 22 years apart, but so close at heart.

• 37:10Speaker 03

  And I'm Lisi DiGiulio, the old one, which means we have wildly different references, occasionally different opinions. And at this point in my 50s, I've lived it all.

• 37:19Speaker 11

  I'm not going to get into your fighting.

• 37:22Speaker 03

  That is wild. I learned that about you today.

• 37:26Speaker 10

  Now in my 30s, being the founder of New Shoes, good taste is my business, and I've always got something to say. If men were just honest about this, there would be so much more peace in the world.

• 37:37Speaker 03

  We're going to talk about dating, relationships, beauty, getting older.

• 37:41Speaker 10

  And a little wiser.

• 37:42Speaker 03

  We're best friends, but we don't always agree.

• 37:45Speaker 12

  Because you told us how accommodating you are. Obviously, I would do what I think I could do to fight the fight, but there's only so much fight I can fight.

• 37:53Speaker 03

  Don't lie to me.

• 37:54Speaker 10

  Don't lie to me.

• 37:55Speaker 03

  Don't lie to me.

• 37:56Speaker 10

  Don't lie to me.

• 37:57Speaker 03

  Don't lie to me.

• 37:58Speaker 10

  Don't lie to me.

• 37:59Speaker 03

  Liar.

• 38:00Speaker 10

  Listen on the iHeartRadio app, Apple Podcasts, or wherever you get your podcasts. I don't really care.

• 38:07Speaker 00

  Welcome aboard season six of The Girlfriends. Flight or Fight, which takes place 30,000 feet in the sky. There's great food, comfortable chairs, and attentive stewardesses. The stewardesses were so beautiful. But in reality, the stewardess job is far less glamorous than it appears. It was the most sexist job I think you could have.

• 38:37Speaker 00

  In this era, the airlines told these stewardesses they have to be single. They had no good excuse for why they wouldn't let women be married. They have to be skinny.

• 38:48Speaker 11

  We were starving ourselves.

• 38:51Speaker 00

  And they have to be young. You would retire at age 32. But one day, a group of stewardesses said, This has got to stop. They risked it all, turning a fight for fairness into a revolution. Listen to The Girlfriends: Flight or Fight on the iHeartRadio app, Apple Podcasts, or wherever you get your podcasts.

• 39:32Speaker 07

  Cholesterol is vital. It is an essential part of all animal life. Without cholesterol, we wouldn't survive. Yet, these crucial functions have been overshadowed by its role in the development of cardiovascular disease. You could say that cholesterol is the Bill Buckner of cell biology.

• 39:56Speaker 05

  Bill Buckner.

• 39:58Speaker 07

  Do you know who that is?

• 39:58Speaker 05

  Why do I know that name? I'm so embarrassed.

• 40:03Speaker 07

  Okay, okay, okay.

• 40:05Speaker 05

  Is this a basketball reference?

• 40:07Speaker 07

  Baseball. This might be a stretch.

• 40:09Speaker 05

  Baseball. Okay.

• 40:11Speaker 07

  But once I landed on it, I was like, I can't let this go. I'm gonna force this analogy.

• 40:17Speaker 05

  Bill Buckner.

• 40:18Speaker 07

  Bill Buckner was a major league baseball player, really a well-rounded player, had over 2,700 hits in over his career, which spanned over 21 seasons, which is huge. Really, he was someone that you wanted on your team.

• 40:32Speaker 05

  Okay.

• 40:33Speaker 07

  Great player. But in the 1986 World Series, while playing first base for the Red Sox, it was the bottom of the 10th inning, and in game six, and he missed a ground ball. It went right through his legs.

• 40:48Speaker 05

  Oof.

• 40:49Speaker 07

  Brutal, right?

• 40:50Speaker 05

  Brutal.

• 40:50Speaker 07

  The error clinched the game for the Mets, and they went on to win the next game, making them World Series champs. And this is like Boston, right? So like, Boston sports fans are known to be incredibly forgiving and understanding.

• 41:05Speaker 05

  They will never forget.

• 41:07Speaker 07

  Yeah. No, I think after the Red Sox won in the 2000s, there was like, you know, okay, we forgive you, Bill Buckner, type of a thing. But it only took almost 20 years.

• 41:19Speaker 05

  I have to know, Erin, did you like already know this about Bill Buckner? How did you?

• 41:23Speaker 07

  I have like, I have felt so compassion, such compassion for Bill Buckner. I think I saw it on some sports special when I was like in high school or something. And I was just like, I was heartbroken because he was so reviled after this happened. And it was one mistake, first of all. I mean, I could go into this. It was also like the pitchers had already blown the lead. It was game six, so they still had one more game that they could have won. But somehow, all of this came down to Bill Buckner.

• 41:52Speaker 05

  You need a guy to blame.

• 41:54Speaker 07

  Yeah, he was a scapegoat, for sure. But that missed ball, the Buckner play, it overshadowed his otherwise really impressive career, and it's mostly what he's known for. So, Bill Buckner, cholesterol, same thing, right?

• 42:11Speaker 05

  Same thing.

• 42:16Speaker 07

  Both, you know, admirable, should be appreciated for more than they are, well-rounded, but they're overshadowed by this bad reputation. The only difference between the two that I could discern is that Bill Buckner is undeserving of the hate that he got, whereas cholesterol has earned its bad reputation, at least in certain contexts.

• 42:38Speaker 05

  I love this. This is, I will never forget this analogy.

• 42:43Speaker 07

  I'm so glad. Cholesterol and Bill Buckner. I don't think it's gonna help anyone studying for a test, but hopefully, it'll bring more appreciation for Bill Buckner.

• 42:55Speaker 07

  Okay, so but today, what I want to do is tell you how cholesterol earned this bad reputation. Our story begins around 2.5 billion years ago with the Great Oxygenation Event.

• 43:07Speaker 05

  Oh, that's not the first time that we've gotten to start this podcast this way, and I just love it.

• 43:12Speaker 07

  It's, I just, I'm like, man, I really, we should just do an episode on that.

• 43:16Speaker 05

  Ooh, yeah.

• 43:17Speaker 07

  I think it was our hemochromatosis episode, when I talked about it, and the importance of iron. But then there was something else.

• 43:23Speaker 05

  You talked about it more recently.

• 43:24Speaker 07

  Yeah.

• 43:26Speaker 05

  Don't know.

• 43:27Speaker 07

  Don't know. But what happened during the Great Oxygenation Event, there was a sharp, sudden rise.

• 43:33Speaker 05

  Boogers. Was it boogers?

• 43:35Speaker 07

  I think it was mucus.

• 43:36Speaker 05

  Might have been.

• 43:37Speaker 07

  That sounds right, yeah.

• 43:38Speaker 05

  I don't know. Sorry.

• 43:40Speaker 07

  Whatever, however it happened, but there was a sharp, sudden rise in oxygen in the atmosphere that was caused by photosynthesizing cyanobacteria. And it had an enormous impact on life on this planet. Although we air breathers don't think of oxygen as harmful, it's actually quite toxic, if you're not used to it, which at the time of the event, described most of the anaerobes that were living on Earth. And so in response to the accumulating oxygen, many organisms died out. Like, it was probably one of the greatest extinction events in our planet's history. But other organisms evolved mechanisms that protected them against oxidative damage, or they developed strategies to take advantage of this molecule, this new molecule, like,

• 44:24Speaker 07

  for instance, aerobic respiration. Cholesterol synthesis, which requires oxygen, evolved after the Great Oxygenation Event, and it dramatically changed things. So you touched on this a bit, but in those early eukaryotes, cholesterol was incorporated into cell membranes, which made for more stable and less permeable barriers. It protected them from oxidative stress. It allowed them to signal across cells, within cells, and it just kind of helped to organize things, which ultimately allowed for greater complexity, even multicellularity, because then you're having like, oh, here's a little organelle that I can have, here's a little whatever. You're not doing open floor concept anymore.

• 45:08Speaker 07

  We are walling off.

• 45:10Speaker 05

  Walling it off, 100%.

• 45:12Speaker 07

  Off. So now, establishing that, so now, fast-forwarding to humans. By the time that our species came onto the scene, cholesterol synthesis had been around for billions of years, and the uses of cholesterol had expanded, became a precursor for hormones involved in stress, reproduction, metabolism. It was essential for staying warm as temperatures dropped and helped to provide enough energy for foraging. It was involved a lot in like, energy balance. And we weren't just making it ourselves, we were also getting it from our diet, which helped to free up energy that could be used for cognitive processing and social behavior.

• 45:52Speaker 07

  Being able to hold on to cholesterol that we got in our diets was really beneficial, particularly because food could become scarce. And so, in some populations, living in certain environments and under certain food availabilities, traits emerged that altered the ways that our bodies dealt with cholesterol. So for instance, it's thought that like, being able to utilize fats rapidly and efficiently would have been really helpful in cold environments, when you needed to keep yourself warm and have enough energy for foraging. And so there might have been a particular pattern of cholesterol regulation that emerged in the people living under these conditions.

• 46:33Speaker 05

  Interesting.

• 46:34Speaker 07

  Right? And so, it's sort of thought that like, the way today that we regulate cholesterol would have been very helpful in the past, but in today's context, it's not really serving us well. We're not faced with these same challenges most of the time.

• 46:50Speaker 05

  Well, and we just also have exposure to much higher levels of dietary fats and things that we would not have had exposure to thousands, hundreds of thousands of years ago.

• 47:00Speaker 07

  Exactly.

• 47:01Speaker 05

  Yeah.

• 47:01Speaker 07

  Yeah. And so, it's again, sort of like this context-specific, something that evolved that was really beneficial under one context, in modern times, maybe isn't as much. You know, much of the world lives a sedentary lifestyle and consumes a diet rich in animal fats, saturated fats, and sugars, where either these types of foods are the ones that are the most readily available. And so, given that the most damaging impacts of high cholesterol tend to happen later in our life, things like heart attack and stroke, it's not really surprising that high cholesterol seems to be a problem for so many of us, right? It's just this sort of constellation of different factors going on.

• 47:41Speaker 05

  Right.

• 47:42Speaker 07

  But again, our relationship with cholesterol, you can't really paint it with a broad brush. It's super complicated, both at a population level, as well as an individual level. Context really does matter with cholesterol. And this rich inner life of cholesterol is what makes it so challenging to understand and to communicate its health impacts. Like, as important as cholesterol is in maintaining healthy physiology, it's also responsible for some major issues. And scientists have suspected this darker side of cholesterol for over a century.

• 48:19Speaker 05

  Wow.

• 48:21Speaker 07

  Yeah. So, since its discovery in the late 1700s, and its naming in 1815, cholesterol, yeah, quite a long time.

• 48:30Speaker 05

  Yeah.

• 48:30Speaker 07

  Yeah. Cholesterol has inspired a great deal of fascination, and over a dozen scientists have been awarded a Nobel Prize for their research on cholesterol.

• 48:40Speaker 05

  Wow.

• 48:41Speaker 07

  Yeah.

• 48:42Speaker 05

  Just for cholesterol.

• 48:43Speaker 07

  Goldmine.

• 48:44Speaker 05

  Really is.

• 48:45Speaker 07

  Yeah. In case you were curious, cholesterol comes from cholesterine, which was the name given to it in 1815 by Michel Chevrel, who had isolated this stuff from human gallstones.

• 48:59Speaker 07

  So chole, like C H O L E is bile.

• 49:02Speaker 05

  Yeah.

• 49:02Speaker 07

  And stereo, solid.

• 49:05Speaker 05

  Solid bile. Okay.

• 49:07Speaker 07

  So when did people start to suspect cholesterol's role in atherosclerosis? The first clue that we have comes from 1910 with a paper by German chemist A. Windhaus, reporting that his patients with atherosclerosis in autopsies, he found that their aortas were just chock full of cholesterol, like much more so than his patients who did not have the disease. The second clue arrives a few years later, in 1913, when Russian experimental pathologist N. N. Anichkow showed that when he fed rabbits basically pure cholesterol dissolved in sunflower oil, they quickly developed lesions in their blood vessels

• 49:50Speaker 07

  that looked a whole lot like human atherosclerosis. The rabbits who were fed on a normal diet did not develop those same lesions. Curious, very curious. And he was inspired to do this not because of Windhaus's paper, but because of other previous work investigating whether too much protein was toxic and caused premature aging.

• 50:13Speaker 05

  Interesting.

• 50:14Speaker 07

  Yeah, which was kind of the idea at the time. And so there were these studies where rabbits were fed on a super protein-rich diet, and the rabbits developed what looked like human atherosclerosis. And so Anichkow wanted to know what it was. Like, was it the protein? Was it, what is it about the protein or that diet specifically that caused the lesions? And so he narrowed it down to cholesterol. Yeah.

• 50:42Speaker 05

  Fascinating.

• 50:43Speaker 07

  Yeah. And so on the surface, Anichkow's results showing that a diet high in cholesterol led to atherosclerosis-like lesions, that's some pretty compelling stuff to our modern eyes.

• 50:55Speaker 05

  Yeah.

• 50:56Speaker 07

  In reality, it did not resonate with the scientific community of the time.

• 50:59Speaker 05

  It never does, does it, Aaron?

• 51:01Speaker 07

  Never does. That's okay. You know, like, there were three main reasons for this hesitance. So the first was that when other people tried to replicate his results in different animals, no dice. It wasn't happening.

• 51:15Speaker 05

  Okay.

• 51:16Speaker 07

  Even when Anichkow himself tried with a dog, he could not produce the lesions. And so he reasoned that it might be because dogs, as omnivores, are more accustomed to eating cholesterol-rich diets and so have evolved to excrete or convert excess cholesterol.

• 51:31Speaker 05

  Oh, interesting.

• 51:32Speaker 07

  He turned out to be right about that, which is cool. Rabbits, being herbivores, don't have that same cholesterol metabolism.

• 51:38Speaker 05

  Right. They're not usually eating cholesterol, so they're not equipped to manage it.

• 51:42Speaker 07

  Yeah. But I don't think other people made this connection. And so they were like, just, I think it's just something about these rabbits. Because I think they also couldn't do it in other animals, like rats, maybe. Anyway. What they were missing also was that this was a two-stage process. You had to have a high cholesterol diet, followed by a corresponding rise in blood cholesterol levels to get atherosclerosis. If you didn't have that second step, if your diet was super high in cholesterol, but you didn't actually have high circulating blood cholesterol, then atherosclerosis probably wasn't going to develop. Because you were lacking the little, the ability to make those plaques.

• 52:22Speaker 05

  You ate it, but then it didn't get stuck in your bloodstream.

• 52:25Speaker 07

  Didn't get stuck.

• 52:26Speaker 05

  And never made it there, for one reason or another.

• 52:27Speaker 07

  Somehow excreted or processed in a different way.

• 52:30Speaker 05

  Never absorbed it, whatever.

• 52:31Speaker 07

  Whatever.

• 52:32Speaker 05

  Just really grody poops.

• 52:35Speaker 07

  Just, yeah, real, real rough, real rough. But the second reason that his results were met with skepticism was the blood cholesterol levels that he was inducing in these rabbits were staggering. It was like 500 to 1,000 milligrams per deciliter and above.

• 52:56Speaker 05

  Of total cholesterol?

• 52:57Speaker 07

  Total cholesterol, yeah. Which is like way higher than it, than it gets for most humans. Yeah.

• 53:03Speaker 05

  If I saw that, I would be, ugh! When I get to the 300s, I'm like, we need to do something. Thank you.

• 53:13Speaker 07

  Oh, just wait till later. I don't know if it's this episode or next, but. But, so it was kind of like, well, yeah, enough of anything is deadly. But like, that's just not realistic. We're not, this is not what we're seeing. Later, though, he showed that even small rises, so not, not 500 to 1,000 range, but like, small rises still led to atherosclerosis-like lesions in these rabbits. It just took longer to develop than like the couple of weeks or whatever it was. And then one last thing, the third thing that held him back, was the prevailing view of atherosclerosis at the time. When his work was being published, atherosclerosis was seen as an inevitable part of the aging process.

• 53:57Speaker 07

  Something that took decades to develop. And so how on earth could these rabbits, showing these atherosclerotic lesions within months or weeks of eating lots of cholesterol, how could that be a reasonable model for human disease? It just didn't seem plausible.

• 54:12Speaker 05

  Doesn't make sense.

• 54:13Speaker 07

  Yep.

• 54:14Speaker 05

  Interesting.

• 54:15Speaker 07

  That skeptical sentiment followed Anichkow for decades as the senescence hypothesis of atherosclerosis proved particularly stubborn to dislodge. For his part, Anichkow pursued this line of research for 50 years. Like, he was like singularly focused on like, I want to understand cholesterol and what's going on here, till the end of his career. And I, I just wrote this little comment here. I wonder too whether global politics came into play, because there's like Cold War stuff. He was friends with Stalin, apparently. And so I'm wondering if there was just sort of like, well, we're gonna distrust you.

• 54:54Speaker 05

  Right. You're not a person that we want to hear from.

• 54:57Speaker 07

  Yeah. Yeah. I don't know. I didn't see that anywhere. That was just my own, my own little speculation. But in any case, the next phase of the cholesterol atherosclerosis story brings us to UC Berkeley in the mid 20th century.

• 55:10Speaker 05

  Oh, wow. A long time later.

• 55:12Speaker 07

  Yeah. Yeah. About 40, 40 years or so, 50 years.

• 55:15Speaker 05

  Okay.

• 55:16Speaker 07

  Yeah. So there, young physician scientist John Goffman found himself drawn to cardiovascular disease, in particular, the relationship between diet, blood cholesterol, and atherosclerosis. And he had come across Anichkow's work, but rather than dismissing it like so many other people, he suspected that there might be something to the cholesterol atherosclerosis link. God, it's so hard to say that over and over again.

• 55:44Speaker 07

  But to get at the heart of that link, pun intended. I literally wrote pun intended here. He, nothing better than a planned joke. But he, he was like, well, I have to better understand the dynamics of cholesterol in the blood. Because by this point in time, researchers had recognized that there were these, these compounds called lipoproteins that circulated in the blood, they carried cholesterol, and they came in different forms. So he was like, there might be, like, this, we can't just say cholesterol. We have to be more detailed than that to understand what's going on.

• 56:18Speaker 05

  Which cholesterol package are we talking?

• 56:20Speaker 07

  Yeah, exactly. And so people had recognized different lipoproteins, but they didn't know what they did and how their concentrations affected health.

• 56:29Speaker 05

  Interesting.

• 56:30Speaker 07

  Unclear. Goffman was really the first to clarify their role. And he did this through a complicated and sophisticated technique. The long and the short of it is that he was able to take a sample and reliably sort and measure the different types of lipoproteins in the blood. And when he applied this technique to the question that interested him the most, what caused atherosclerosis, he found that not all lipoproteins had the same impact. And he proposed that we shouldn't be looking at total cholesterol. That's an incomplete picture, or that's too broad of a picture. Really, you need to give different weight to the different lipoproteins in predicting the risk of cardiovascular disease.

• 57:14Speaker 07

  So in other words, he came up with the atherogenic index. He was like, we need to, we need to figure this out and have these specific numbers. And he applied this index to a small sample of patients. And he showed that there was a strong association between certain ratios of lipoproteins and the risk of heart attack.

• 57:35Speaker 07

  As a fun little aside here, his wife, Dr. Helen Goffman, published what was probably the first heart-healthy cookbook in 1951. I think because of this research was like, don't eat saturated fats, basically.

• 57:52Speaker 07

  Goffman's research, though, really transformed the field. He bears the title, "The Father of Clinical Lipidology."

• 58:00Speaker 05

  Wow.

• 58:00Speaker 07

  I know.

• 58:01Speaker 05

  Gotta love it. Gotta love it when we get a father.

• 58:03Speaker 07

  Yeah, we have, we have another father in the next episode. The father of statins. Yeah.

• 58:11Speaker 07

  But his central hypothesis, linking certain cholesterol-carrying lipoproteins with heart disease, once again, it met with resistance.

• 58:19Speaker 05

  Hmm.

• 58:20Speaker 07

  Understandably so, to a degree. So first of all, he didn't have a mechanistic explanation as to why this would cause disease. That would have to wait for a few decades. And secondly, his sample sizes were fairly small. They weren't prospective, meaning you couldn't draw firm conclusions about causality. Like, which came first? Was it cholesterol or heart disease? Did you have heart disease and that is what caused your high cholesterol?

• 58:45Speaker 05

  Right.

• 58:46Speaker 07

  So doubt lingered.

• 58:47Speaker 05

  Hmm.

• 58:48Speaker 07

  And things were getting heated. The quote-unquote "cholesterol wars" that began in the 1950s reached new heights in the 1970s. Oh, yeah. Cholesterol wars, decades long.

• 59:01Speaker 05

  Cholesterol wars, more than salt wars.

• 59:03Speaker 07

  Honestly, very, like, I would say more contentious than salt wars.

• 59:08Speaker 05

  Interesting.

• 59:09Speaker 07

  In my reading of it, yeah.

• 59:10Speaker 05

  Tell me all about it, Erin.

• 59:12Speaker 07

  Yeah. Okay, so while some physicians and scientists had grown convinced that high blood cholesterol caused heart disease, others argued that it was the other way around, and they took issue with "high." Where do you draw the line? What does "high" mean?

• 59:28Speaker 05

  Okay.

• 59:29Speaker 07

  Yeah, yeah, okay. So, in medicine, one common cutoff for deciding this is 95%. So, for example, if 95% of people have cholesterol less than a particular value, anything above that is considered abnormal.

• 59:45Speaker 05

  Mm-hmm.

• 59:46Speaker 07

  The problem with this is that you're assuming any cholesterol value less than 95% is normal, non-pathogenic.

• 59:55Speaker 05

  Right.

• 59:56Speaker 07

  But "average" doesn't always equate to "normal."

• 59:59Speaker 05

  Mm-mm.

• 1:00:00Speaker 07

  In the 1940s, 95% of the US population had blood cholesterol below 280.

• 1:00:06Speaker 05

  280?

• 1:00:07Speaker 07

  280.

• 1:00:08Speaker 05

  95%.

• 1:00:09Speaker 07

  We know today that, yeah, that heart attacks occur with levels much lower than that. In fact, most occur between 200 and 280. But since that was the standard cutoff at the time, doctors didn't consider a cholesterol level of, say, 250 to be worrisome, because it was considered normal.

• 1:00:26Speaker 05

  And this is total cholesterol they're still looking at?

• 1:00:28Speaker 07

  Total cholesterol, yes, yes. It took several strong epidemiological studies to turn that thinking around and say, like, actually, "average" doesn't always equate to "normal," healthy.

• 1:00:39Speaker 05

  Right.

• 1:00:40Speaker 07

  So, one of these studies, I actually touched on in a previous episode, our dietary guidelines episode.

• 1:00:46Speaker 05

  Okay.

• 1:00:47Speaker 07

  Ansel Keys's seven countries study.

• 1:00:49Speaker 05

  Mm-hmm.

• 1:00:50Speaker 07

  So, in the 1950s, as a refresher, Keys and his colleagues conducted a wide-ranging study across seven countries examining relationships between diet, blood cholesterol, and mortality due to coronary heart disease. The results were striking. At one end of the spectrum, you had Japan, with an average blood cholesterol level of 160 and less than five fatal heart attacks per 1,000 men.

• 1:01:15Speaker 05

  Okay.

• 1:01:16Speaker 07

  On the other end, you've got Finland, with a blood, an average blood cholesterol of 260 and 70 fatal heart attacks per 1,000.

• 1:01:25Speaker 05

  Oh!

• 1:01:26Speaker 07

  Yeah. And other countries kind of followed the same trend, just like, fell right on, along that plotline, with blood cholesterol and saturated fat consumption positively related to fatal heart attacks.

• 1:01:38Speaker 05

  Yep.

• 1:01:39Speaker 07

  Again, it was compelling stuff, but, again, like in many other studies, it showed correlation and it didn't prove causation, and so a lot of people remained unconvinced. The next study turned all but the most stubborn skeptics into believers.

• 1:01:55Speaker 05

  Okay.

• 1:01:56Speaker 07

  In 1950, researchers enrolled 28,000 residents of Framingham, Massachusetts.

• 1:02:02Speaker 05

  Love it, Framingham!

• 1:02:04Speaker 07

  Framingham. The Framingham study is one of the most, is one of the most long-term and valuable and informative public health studies ever put together.

• 1:02:14Speaker 05

  It's incredible.

• 1:02:15Speaker 07

  It's incredible.

• 1:02:16Speaker 05

  Yeah.

• 1:02:17Speaker 07

  They, they measured things like blood cholesterol, blood pressure, smoking, diabetes, and family history of disease, and they followed these residents for years. It is still ongoing, recording any disease events as they occurred.

• 1:02:30Speaker 05

  Including in offspring now.

• 1:02:32Speaker 07

  Including in offspring.

• 1:02:33Speaker 05

  They've enrolled offspring, like, it's, it is a huge deal type of study that's been ongoing for so long.

• 1:02:38Speaker 07

  The, the amount of information we've gained, really cool, really, yeah, powerful. Okay. But what this allowed them to do, what the study allowed them to do, was establish a sequence. High cholesterol preceded heart attack, and then they could also calculate risk. What is high cholesterol? How much does smoking, combined with high cholesterol, impact risk? Things like that. They could create these sort of calculations and say, what are the factors that increases your risk of heart attack or stroke?

• 1:03:10Speaker 05

  Yeah.

• 1:03:11Speaker 07

  Where the seven-country study showed the relationship between blood cholesterol and heart disease at a population level, the Framingham Heart Study demonstrated it in the individual. So this person had high cholesterol, and then they experienced a heart attack.

• 1:03:28Speaker 05

  Mm-hmm.

• 1:03:29Speaker 07

  It was sort of that directional relationship.

• 1:03:30Speaker 05

  Right.

• 1:03:31Speaker 07

  The link between high cholesterol and coronary heart disease could not be ignored.

• 1:03:37Speaker 05

  No!

• 1:03:38Speaker 07

  No. Which, of course, didn't prevent people from doing so. The wars continued, Erin.

• 1:03:43Speaker 05

  Yeah, wow.

• 1:03:45Speaker 07

  But increasingly, those cholesterol doubters were becoming a tiny but vocal minority. Other studies, such as dietary intervention studies, helped to build the case against cholesterol, but there was still one important facet missing, and that was a mechanism.

• 1:04:01Speaker 05

  Hmm.

• 1:04:02Speaker 07

  So since at least the late 1800s, physicians had noticed a condition that ran in some families, where people developed large deposits of lipids under their skin. Members of these families were very prone to develop severe cardiovascular disease at early ages, with some experiencing heart attacks in the first 10 years of life.

• 1:04:20Speaker 05

  Gosh.

• 1:04:21Speaker 07

  And by the early 1970s, researchers had established that very high blood cholesterol was a key feature of this, hence the name familial hypercholesterolemia.

• 1:04:32Speaker 05

  Mm-hmm.

• 1:04:33Speaker 07

  But they weren't sure what caused it, or its, its role in disease development particularly. They were like, okay, there's clearly a genetic link, but like, what's the mechanism here? What is that mutation that leads to these high cholesterol levels?

• 1:04:46Speaker 05

  Exactly. What is going on that is causing this person's cholesterol to be so high?

• 1:04:51Speaker 07

  Yes.

• 1:04:52Speaker 05

  And then resulting in negative health outcomes? Like, what's, why?

• 1:04:56Speaker 07

  Why?

• 1:04:57Speaker 05

  Why?

• 1:04:58Speaker 07

  Why? In 1973, the key to the puzzle was unlocked by two researchers, Michael Brown and Joseph Goldstein, who, over the course of their 50-year collaboration, would be compared to Rogers and Hammerstein.

• 1:05:12Speaker 05

  I love it.

• 1:05:13Speaker 07

  Which is so, I love that.

• 1:05:15Speaker 05

  Yeah. Erin, can we work together for 50 years?

• 1:05:18Speaker 07

  Yes, yes. I was like, can that be us? I want that to be us.

• 1:05:22Speaker 05

  Please, thank you!

• 1:05:23Speaker 07

  Yes.

• 1:05:24Speaker 05

  I don't think we'll ever create something as good as Rogers and Hammerstein, though. Let's be, let's be real.

• 1:05:30Speaker 07

  Or the LDL receptors.

• 1:05:31Speaker 05

  Goldstein, yeah.

• 1:05:32Speaker 07

  Yeah. But Brown and Goldstein, they were fascinated by the mystery of familial hypercholesterolemia, and they wanted to figure out what caused such high levels of LDL in the blood in affected individuals, because that was really one of the key features of this, was high LDL. As they discovered, it wasn't that there was too much LDL being produced, it was that too little LDL was being taken up by the cells.

• 1:06:01Speaker 05

  Ah! I love this so much, Erin.

• 1:06:03Speaker 07

  So the cells of people with familial hypercholesterolemia lacked receptors that would allow them to scoop up the LDL from the bloodstream. So they didn't have those little Velcro hands.

• 1:06:14Speaker 05

  Right.

• 1:06:15Speaker 07

  They didn't have enough Velcro hands.

• 1:06:16Speaker 05

  Not enough Velcro hands.

• 1:06:17Speaker 07

  And so LDL just kept piling up, piling up, circulating and circulating with nowhere to go, and over time, it just, again, it's a numbers game. It's going to lodge into the blood vessel walls, it's going to cause a blockage, inflammation, plaques, et cetera, et cetera.

• 1:06:30Speaker 05

  Huh.

• 1:06:31Speaker 07

  Yeah. This discovery, Brown and Goldstein's discovery of the LDL receptor, it transformed the field.

• 1:06:38Speaker 05

  Wow.

• 1:06:39Speaker 07

  So much so, that it earned them a Nobel Prize in 1985.

• 1:06:43Speaker 05

  Wow.

• 1:06:44Speaker 07

  Because not only did it explain why people with familial hypercholesterolemia develop cardiovascular disease, it clarified how our cells regulate cholesterol, specifically LDL, and why disease happens when that regulation goes awry.

• 1:06:59Speaker 05

  Mm-hmm.

• 1:07:00Speaker 07

  So it was a major, major step forward in solidifying the cholesterol-heart-disease link, and it opened these different pathways to treatment.

• 1:07:07Speaker 05

  Ding ding ding.

• 1:07:09Speaker 07

  Can we do something about this receptor?

• 1:07:11Speaker 05

  Right.

• 1:07:12Speaker 07

  For instance, yeah.

• 1:07:13Speaker 05

  Yeah.

• 1:07:14Speaker 07

  Did it end the cholesterol wars? Not necessarily.

• 1:07:18Speaker 05

  Oh!

• 1:07:19Speaker 07

  It really didn't. The debate continued, but it had lost a lot of steam. The advent of cholesterol-lowering drugs, like statins, changed the conversation by turning cardiovascular disease from a disease to manage into one to treat, even prevent, potentially.

• 1:07:38Speaker 05

  Or prevent, yeah.

• 1:07:39Speaker 07

  But as we'll see next week, their use has also been met with a hefty amount of skepticism, and so the cholesterol wars really continue through today.

• 1:07:47Speaker 05

  It is so interesting, Erin, how much, like, it, it is really hard, I think, to find someone who doesn't at least agree that high levels of cholesterol put you at high risk for heart disease.

• 1:08:02Speaker 07

  Yeah.

• 1:08:03Speaker 05

  And yet, there still is so much, like, wah, wah, wah, about what you do about it, or what we shouldn't do about it, or what your diet effect might be. Like, it's, oh, I can't wait for next week.

• 1:08:15Speaker 07

  Yeah, there's, there's a lot more to cover next week when it comes to the story of statins and how the role that they have played in changing our approach to managing and preventing heart disease. Also, how the heck do statins work? Do you want to know the answers to these questions?

• 1:08:32Speaker 05

  I want to tell you them.

• 1:08:33Speaker 07

  Tune in next week.

• 1:08:37Speaker 05

  Should we tell people if they want to just learn more about what we've already talked about?

• 1:08:41Speaker 07

  Yes, absolutely, we should. I have a lot of sources for this.

• 1:08:45Speaker 05

  I bet you do, Erin.

• 1:08:46Speaker 07

  I'm shouting out, so there was a, if you wanted to learn more about sort of cholesterol in oxygen and the Great Oxygenation Event and why it plays a role, there's a paper called "The Evolution of Cholesterol-Rich Membrane as Oxygen Adaptation: The Respiratory System as a Model" by Zuniga, Hertz, and Patel from 2019. I liked that one. And then there's an excellent series by Steinberg from 2004. It's a five-part series called "An Interpretive History of the Cholesterol Controversy." Contro- controversy. I can't speak today, Erin. It's a five-part series, check it out. Good, good stuff.

• 1:09:23Speaker 05

  You did a good job, I think.

• 1:09:25Speaker 07

  Thanks.

• 1:09:26Speaker 05

  I also had a number of papers for this episode. I think probably my three favorites that cover a lot of ground. One was from 2020 by Luo et al. from Nature Review's Molecular Cell Biology. It was called "Mechanisms and Regulation of Cholesterol Homeostasis." So this is just like how our bodies are using cholesterol. There was another older one by Maxfield and Tabas from 2005 in Nature called "Role of Cholesterol and Lipid Organization in Disease." And then one from 2019 by Holmes and Alaa Corpella from Nature Review's Cardiology, just titled "What Is LDL Cholesterol?" So that was a good one, too. But they have a bunch more, and you can check them all out from like these ones from this

• 1:10:10Speaker 05

  episode, but also from all of our other episodes on our website, thispodcastwithkylie.com, under the Episodes tab.

• 1:10:17Speaker 07

  Indeed. Thank you again so much, Tori, for sharing your story with us. It means a lot.

• 1:10:22Speaker 05

  It really does. Thank you.

• 1:10:24Speaker 07

  Thank you also to Blood Mobile for providing the music for this episode and all of our episodes.

• 1:10:29Speaker 05

  Thank you to Liana and Tom and Mark and Jessica and Christine, everyone, everyone. I had exactly right.

• 1:10:37Speaker 07

  Yes.

• 1:10:38Speaker 05

  We really appreciate everything that you do for us.

• 1:10:40Speaker 07

  We do. Thank you to you listeners for listening, watchers for watching, anyone who subscribes, participates, does anything with this podcast, interacts in any way, we truly appreciate it.

• 1:10:51Speaker 05

  We do, thank you. And as always, a special shout out to our patrons for your support over on Patreon. It means so much to us.

• 1:10:58Speaker 07

  Truly.

• 1:10:59Speaker 05

  Thank you.

• 1:11:00Speaker 07

  Truly, thank you. Until next time, wash your hands.

• 1:11:03Speaker 05

  You filthy animals.

• 1:11:32Speaker 13

  This is Ashley Canetti from the Ben & Ashley I, almost same as Podcasts. You know that feeling when your skin just needs a tall drink of water? That's what Clinique Moisture Surge 100-Hour Moisturizer is for. Moisture Surge 100-Hour Moisturizer absorbs instantly and hydrates for 100 hours for plump, glowing skin. That's right, 100 hours. It's a lightweight, oil-free gel cream, safe for sensitive skin, it's allergy-tested and fragrance-free. So try Clinique Moisture Surge 100-Hour today at clinique.com. Feels like Moisture Surge.

• 1:12:08Speaker 10

  Lisa, tell them about our new show.

• 1:12:11Speaker 03

  We have a new podcast. It's called Don't Lie to Me.

• 1:12:14Speaker 10

  I'm Lexi Yuanu. We're two best friends, 22 years apart, but so close at heart.

• 1:12:19Speaker 03

  And I'm Lisi DiGiulio, the old one, which means we have wildly different references, occasionally different opinions, and at this point in my 50s, I've lived it all.

• 1:12:28Speaker 10

  Now in my 30s, being the founder of New Shoes, good taste is my business.

• 1:12:33Speaker 03

  Listen on the iHeartRadio app, Apple Podcasts, or wherever you get your podcasts.