Over the past few decades, an abundance of scientific research has focused on resveratrol, a plant-based compound found in red grapes and peanuts. Much of this research has demonstrated that, at high doses, resveratrol exerts beneficial health effects – especially on the cardiovascular system – and has been shown to ameliorate the deleterious effects of an obesogenic diet in monkeys. Resveratrol is a "dirty molecule," however, known for its multiple cellular targets, so teasing out all the ramifications of its use has proven problematic. Furthermore, it is relatively unstable and demonstrates poor bioavailability in humans. In this clip, Dr. David Sinclair identifies some of the practical considerations of resveratrol supplementation and discusses his personal use of the compound.

Rhonda: You know, the resveratrol field, when I first was following it back in, I guess, the early 2000s, you know, I was very skeptical that there would be any effect in humans taking resveratrol because, certainly not from drinking a glass of wine. But from supplementing, just because it seemed as though, like, the doses required to get some really beneficial effects, at least in some of the rodent studies seemed sort of, you know, high and it didn't seem very attainable. But as you know, there was a really sort of compelling primate study in rhesus monkeys. I forgot when that was published. It was like mid-2000s, or 2011, or something like that.

David: Right. Rafa de Cabo's group with NIH.

Rhonda: Yes, that's right. They gave these rhesus monkeys resveratrol, and I think they started out with a lower dose, like 80 milligrams per kilogram and they went up to, like, 480. Any reason? Do you know why they start with... I've seen more than one study do that.

David: Yeah. So just anecdotally, what Rafa told me, I think, is that they started at the low dose and didn't see a change in pulse wave velocity in the blood vessels, so they upped it and then that's where they saw the benefit.

Rhonda: Oh, okay. Well, this study was... You know, the doses were very doable on humans when you, you know, convert and basically, you know, feeding these monkeys, they're feeding them, like, this terrible high sucrose diet, high sucrose and high fat, and they, like, it caused them to have, like, 40% increased aortic stiffness, but the resveratrol completely ameliorated it, like... So I was like, "Holy crap, that's pretty cool." I think that was the one study that sort of changed my view and then I started to sort of get into the literature and read ones that there was, you know, there's been a variety of clinical studies, as you know, and...

David: Yeah. Well, I'm glad somebody is reading the literature. Because there was a "hate me" club with resveratrol because it got so much attention. And anything that gets a lot of attention gets the "hate me" club in reverse. But resveratrol, I still take resveratrol, probably a gram or so every morning.

Rhonda: A gram? Really?

David: Yeah. In my yogurt. I don't measure it out, I just shake it in. So it might be half a gram to a gram.

Rhonda: Is this from your own, like, stash or is it like a...

David: It's a stash in the basement. I've had it for years.

Rhonda: It's a private stash?

David: It is. I'm not a drug dealer.

Rhonda: Because I don't usually find doses of resveratrol above 250 milligrams, I think.

David: Yeah. Right. You made a good point, which is it's a really insoluble molecule and that's one of the... Well, there are two problems with resveratrol, one is it's really insoluble. So if you just give it as a dry powder to an animal or a human, it's less likely to get absorbed. We know that as a fact. Include it with a bit of fat, it'll go up five to tenfold in the bloodstream.

Rhonda: Really?

David: It's like a big effect we've seen in mice and monkeys, it was with a bit of fat in the diet as well. And then the second problem with resveratrol is that it's light-sensitive. And so those people who...researchers who put it in a plate with worms or didn't treat the molecule with respect, it goes brown. It goes off. It's one of the reasons it's very hard to put in a cosmetic because your cosmetic will turn brown. If you use brown resveratrol, it won't work. So you've got to keep it in the dark, in the cold, and it'll be fine.

Rhonda: Okay. So...

David: Or in a basement.

Rhonda: ...cold, dark, and also I think there's various forms like trans-resveratrol.

David: I'd go for the trans because when we gave the cis form to the sirtuin enzyme, it didn't activate it, but the trans worked brilliantly. Yeah. Rafa de Cabo, actually, he's been a good friend over the years. A great colleague. He did the study with us on the mouse, resveratrol study that showed that on a high-fat diet, those mice were extremely healthy and longer-lived and their organs, when they opened up the mice, they were pristine. So the mice were still obese, so we didn't give them a lot of resveratrol, it was pretty low dose, but their organs were so beautiful. Their arteries, when you stain them for oil or fat, it was night and day. The ones on resveratrol or the ones without resveratrol were stained with fatty lumps. resveratrol, clean. And that alone makes me say, you know, resveratrol's probably not going to hurt me and it may very well help my cardiovascular system.

Rhonda: It seems to be really important for a cardiovascular system, like... And I'm just kind of, do you know why, why is it...?

David: We have a number of ideas. And resveratrol is a dirty molecule, so there's not just one way it works. Sirtuins definitely are involved. We now have a mouse that's mutant for the resveratrol activation of SIRT1, so we now see that some aspects, like endurance, of resveratrol seem to be through SIRT1. So one of the effects is through SIRT1's anti-inflammatory actions in the lining of the blood vessels, the endothelial cells.

Rhonda: Oh. Okay.

David: Yeah. That seems to be important. And there's other aspects also in DNA repair as well. infiltration of macrophages in there seems to be dampened. And we also looked at oxidative stress in those arteries of those mice treated and it was way down in the resveratrol mice.

Rhonda: Yeah. With the rhesus monkeys, with the, you know, basically like, you know, completely reversing that 40% aortic stiffness, that's like pretty, it's a pretty dramatic effect. So I was...

David: It is. And so, yeah, I think resveratrol, it's... People are, you know, "Oh, is it true, is it not?" "60 Minutes" did a story and then there was an argument about how it was working. And so people are confused about the molecule, and I still stand by it because the results, like you say, in animals. And there are clinical studies now that are really positive in humans. Not all of them, sometimes it has no effect. There was one study where it interfered with endurance exercise. Don't understand that.

Rhonda: Metformin was kind of shown to do something similar where it prevented mitochondrial adaptations in [crosstalk 00:47:47] but who knows?

David: I mean, maybe... Rhonda, what's maybe happening is that if you're dampening free radicals too much, you're actually losing that benefit.

Rhonda: Hormetic effect.

David: Exactly. The mitohormesis. But I haven't seen any downside. You know, I'm a N-of-one, as you would say, in a clinical trial. I've had my heart checked out with a 3D movie MRI. My heart looks like it's 20, it's got no sign of aging. So, it doesn't seem to be doing myself and my dad any harm. So...

Rhonda: How long have you been taking it?

David: Oh, geez. Since 2003.

Rhonda: Wow. And you take about a gram [inaudible 00:48:22] or so a day.