Dr. Benjamin Levine: So we partnered with the Dallas Heart Study, a large, community-based, very highly intensive epidemiologic study. And we looked at people who were in their thirties, in their forties, in their fifties, in their sixties, in their seventies, and we did the same studies on them. And what we found is that the heart starts to shrink in that late middle-age period. You know, if you think about aging at so late middle age is kind of that 50 to 65 period, early middle age is at 35 to 50 range.

Dr. Benjamin Levine: So the heart will get a little bit stiffer, but it's in that late middle range that starts to atrophy and get really, you see the most dramatic effects of aging. So we said, okay, well, is this all reversible? That was sort of the question you asked me earlier. And so we took our healthy seniors and we trained them for a year. We used the same training program that we used in a group of young people trying to make them endurance athletes. Well, I know you want to chat about that a little bit also. But we put them… We trained them hard, and they got fitter for sure. But we didn't change the heart structure at all, not even a little bit. So once you got to be age 70, it was virtually impossible to change the heart structure.

Dr. Benjamin Levine: That was very disappointing because we really thought we were going to be able to reverse it. And when we trained our young people, we saw very marked and very impressive increases in cardiac size and compliance and things like that. But we said, okay, what if we made a mistake? What if we started too late? And what if we didn't train them long enough? And what if we didn't train them hard enough? So we then said, okay, let's take a group of those late middle-agers in the sweet spot, let's train them hard, train them increasingly fit over a year, and then sustain that at our perfect dose, that four to five days a week, and we'll do that for two years.

Dr. Benjamin Levine: And lo and behold, we were able to reverse the effects of sedentary aging by sustained training at the right dose at the right time period in the aging process. So that paper, which was published in Circulation, got a lot of press. It still is among the top ten papers for something called Altmetric, which is the interest within the media and the public and the, the professional community, the top ten in the history of Circulation, which is the American Heart Association journal.

Dr. Rhonda Patrick: Incredible. How much would you say the heart aging was reversed in these mid-late? Was it late middle age? 50-year-olds?

Dr. Benjamin Levine: Yeah, 50-year-olds. So the answer to that is, from the standpoint of the youthfulness, the compliance of the heart, most of it. So we didn't get quite back to being a healthy 30-year-old, but we got pretty close. So there are a lot of other things that happen with aging that are not just related to the sedentariness of the circulation. Of course, one of the things that happens is you get accumulation of advanced glycation end products. You know what those are?

Dr. Rhonda Patrick: Yeah. Tell the audience, please.

Dr. Benjamin Levine: Yeah, yeah. So those are the things that. Not you, Rhonda, but other people stiffen your skin and cause wrinkles. We measure it in diabetics with hemoglobin A1c. It's a natural biologic chemical reaction called the Maillard reaction. Your audience is probably more familiar with it from basting a turkey. What do you think causes that crinkling and stiffening of a skin when you baste a turkey, it's this reaction, this complexing of glucose, sugars with carbohydrate, with collagen. And it happens in the skin, it happens in the blood vessels. It happens in the heart. So we actually gave a drug, which doesn't exist anymore. I have the last of it in my laboratory that breaks advanced glycation end products. And we gave it to another group of healthy sedentary seniors.

Dr. Benjamin Levine: And one group just got the advanced glycation end-product inhibitor. One group got a placebo, another group did a year of training, just training. And another group did the advanced glycation end product and training. So four groups just taking the advanced glycation end product inhibitor didn't do anything. It worked in animals. We saw a marked improvement in rats. Nobody really cares that much about that because we're not rats. But it didn't help the sedentary humans. And once again, we saw that a year of training didn't do anything. But when we added the training and the advanced glycation end product inhibitor, we had about the equivalent of a 15-year reduction in the apparent vascular age of the circulation.

Dr. Rhonda Patrick: In 70-year-olds.

Dr. Benjamin Levine: Yeah, in 70-year-olds. That's right.

Dr. Rhonda Patrick: So the advanced glycation end products, it's interesting because it's very, as you mentioned, tied to blood glucose regulation. And of course, people with type 2 diabetes are the extreme case where. Or type 1 as well, like, they're not able to regulate their blood glucose and have probably the most risk of having higher levels of advanced glycation end products and vascular damage. So you mentioned the heart aging, and you talked about, I don't know if you started with when this starts, but the stiffening, you said is stiffening until about middle age, and then it starts to shrink. Is that correct?

Dr. Benjamin Levine: That's right.

Dr. Rhonda Patrick: So the question is, it's interesting that you were able to reverse this cardiac aging in these late middle-aged folks.

Dr. Benjamin Levine: Late middle age, yeah, 50 to 65. That's our late middle-aged target.

Dr. Rhonda Patrick: So you're already stiffening the blood vessels at that point.

Dr. Benjamin Levine: Yeah, you're probably having some stiffening. That's exactly right. It's not fully ensconced. It's still reversible by then.

Dr. Rhonda Patrick: Okay. So the question is, it'd be interesting to see if there were a subset of people, too, that, let's say, had very low HbA1c or something that did respond.

Dr. Benjamin Levine: It's a good question, Rhonda. And if you think about it, hemoglobin, which is what we're talking about when we measure hemoglobin A1c that lasts for 120 days, those red cells don't last forever. That's why hemoglobin A1c is such a good marker of diabetic control. Blood glucose is measuring your glucose instantaneously. Hemoglobin A1c is measuring the average over the last few months because that's how long hemoglobin lasts. But collagen lasts forever, so once you've glycated it, it's done. And that's why measuring glycated products in the skin or in the vasculature is a marker of something over an even longer time scale. We hoped to be able to break all those. To be honest with you, I'm not sure that we did. The animal data is very compelling.

Dr. Benjamin Levine: We did not actually take cardiac biopsies to prove that we had broken the advanced glycation end products. We just used the physiological consequence. And so one could argue that we didn't even do what we thought we did. But I think I was impressed enough by the combination of exercise training and breaking the AGEs. I'll use the acronym for simplicity's sake, that I do think it plays some role. It's obviously not the entire issue, because just breaking them by themselves didn't do anything. But the combination of the stretching of the blood vessels and the heart during exercise is perhaps enhanced, or was perhaps enhanced by breaking the advanced glycation end products.

Dr. Rhonda Patrick: So what would you say to someone who's in their seventies, that's been sedentary and wants to train four to five days a week? And so you're talking about this two-year study. I mean, I've read the methods section, too, and it's quite impressive. I mean, these people are, you know, they're doing a lot of physical activity and including vigorous intensity exercise, you know, where they're doing very intense exercise at least once, maybe twice a week. So what would you say to someone who's in their seventies? I mean, how can they improve their cardiovascular health?

Dr. Benjamin Levine: So I'm not saying that we should throw our hands up and saying, oh, it's too late. Cause that's clearly not true. Right. I will say, if you hope to overcome 70 years of bad behavior, of bad diet and sedentariness and smoking, you can't make that up with a couple of years of exercise training when you turn 70. That being said, there are a lot of other benefits to exercise training that are not related to cardiac structure. Right. You improve endothelial function. What I mean by that is the arteries have a lining inside them. That is, it's not like a lead pipe. It's actually alive. It's biological, and it allows for that smooth flow of blood. And then as you need more blood, like during exercise, those blood vessels start to expand.

Dr. Benjamin Levine: So the endothelium relaxes and opens up the blood vessels, and it's damaged the endothelium with cholesterol and hypertension and smoking over years that causes atherosclerotic disease. So it's a very important biologic phenomenon that is clearly improved by exercise training at any point in life. So I think that's really helpful. I think we know that exercise training alters the autonomic control of the circulation. The autonomic nervous system is that part of the brain and the nervous system that regulates those things that we don't have to think about. Like, you're not sitting here saying, what's my heart rate? Is it 60? Is it 50? How do I make it 62? That just happens in the background, right? And the autonomic nervous system has a brake, which is the parasympathetic nervous system.

Dr. Benjamin Levine: You've heard the term "vagal responses." And an accelerator, that's the sympathetic nervous system. And you're constantly balancing the brake and accelerator throughout your life. During exercise, you take your foot off the brake, you withdraw the vagus nerve, and you increase the sympathetic nerve. That's what speeds the heart rate during exercise. And that comes from signals in skeletal muscle. That's how your brain knows what to do during exercise. So we know that if you… This is going to be a little bit… I'm going to take a step back for 1 second.

Dr. Benjamin Levine: We know that if you have an acute heart attack and if I, in a dog, if I tie off a coronary artery with a little snare while they're running on the treadmill, some dogs will develop ventricular fibrillation and have a cardiac arrest, and they'll do it every single time. And if we resuscitate them, and then we put them on the treadmill and stimulate the vagus nerve to the heart and tie off the coronary, none of them have ventricular fibrillation. They don't die. And if you train them before you tie off the coronary artery without even stimulating the vagus nerve, you have the same effect. So the ability to increase vagus tone or neural activity in that parasympathetic nerve may be very protective against sudden cardiac death.

Dr. Benjamin Levine: And those things will happen even if you start training in your seventies. Lastly, of course, is people get fitter. We know I can make them fitter. I told you that. And that's good. That's important because unfortunately, with aging, you get less fit. Even if you're a master's athlete, you get less fit. I would be a fool if I sat here in front of you and told you that exercise training can completely prevent the aging process. I wish that it could, but it doesn't. But one of the most important things is that it preserves your aerobic power. This VO2 max. And so think about a cliff, right? And you're heading towards that cliff with aging.

Dr. Benjamin Levine: And that cliff is where the maximal effort that you have in your body that you can do is what you need to do–activities of daily living, that's in that three to four metabolic equivalents –METs–the amount of oxygen you need to just sit here quietly, three and a half milliliters of oxygen per minute, per kilogram of body mass. And once you get to that, you're really kind of in trouble, right? Because then everything you do in life is a maximal effort. Well, if that point is here and you're a masters athlete and you're up here, when you're young and you train all your life, you stay above that really well.

Dr. Benjamin Levine: If now you're unfit and you don't exercise your life and you're heading towards that cliff, what you want to do is change that trajectory and either push it up or flatten the curve a bit so that you prolong that period before you become disabled. And that comes down to both endurance training and strength training because you need both of those to be able to maintain functional capacity.