[Ira Flatow:] Here's some news to raise a glass to: the idea that red wine may help us live longer and healthier lives. Well, it got a new boost this week. According to a team of researchers, a compound found in the skin of grapes could be an antidote to aging by slowing down the process and even fending off disease and inflammation associated with getting old. It's the topic of a new study published this week in the journal Science. But before you pop the cork on that merlot, this story doesn't end there. The study's researchers are hoping these findings will help drug companies develop anti-aging drugs to treat diseases like Type 2 diabetes, heart disease and even obesity. Sound too good to be true? Well, my next guest is here to talk about it. David Sinclair is professor in the Department of Genetics at Harvard Med School in Boston. He's lead author of the study that was published this week in Science. He joins us from California. Welcome to SCIENCE FRIDAY.
[David Sinclair:] Hi, Ira, thanks for having me on.
[Ira Flatow:] Are we talking about resveratrol here?
[David Sinclair:] Well, the resveratrol discovery was about 10 years ago. We, my colleagues and I, made that discovery. But what we've done since then is use that as a just a stepping stone, a proof of concept to make much more potent synthetic drug-like molecules that are just in the beginnings of human clinical trials. And this paper is about the finding that these molecules from grapes and the synthetics all seem to work through this one particular gene, genetic pathway we call the sirtuin pathway.
[Ira Flatow:] Let's back up a little bit and talk about the study you did in mice. What did you find what did you give the mice, and what did you find there?
[David Sinclair:] Well, originally we found resveratrol just in a test tube, looking for molecules that would turn on this enzyme, this protein that seems to defend against diseases in aging. We then moved to nematode worms and flies. We've done some work with bees even. The mouse study was in 2006. These were mice that were fed a Western diet. They were chubby, and they were developing usual signs of disease that we see in elderly obese people. The mice that had the resveratrol in their diet were still obese, but they were seemingly or relatively immune to the effects of the obesity. So their arteries were clear, their liver was nice and thin. Their bones were stronger. They could run further. And so that was really the first evidence that we were on to something important for potentially for human health.
[Ira Flatow:] And so then you identified the action of how the molecule works.
[David Sinclair:] Right, so that's what we've been doing for the last few years, is trying to figure out, first of all we've been criticized for this. It does sound too good to be true. And turning on proteins rather than just inhibiting them is fairly rare in drug development and even biology. So this was, on multiple levels, seemingly too good to be true, and what we've done in this paper with my colleagues, and there are actually 30 authors that I'm here representing, we were able to, I think, very well demonstrate how these molecules work not just in the test tube but even within cells, hitting a very precise part of this protein that we think controls health and possibly aging.
[Ira Flatow:] Well, give us some of the details of that. When you mean it controls aging and these other miraculous-sounding things, give us some idea of what you're talking about.
[David Sinclair:] Well, it's important to know that I'm also here representing a field of scientists, probably hundreds of labs around the world who are focused on finding what are the causes of aging and more important, actually, the genes that can slow that down. And we know of probably 100 of these genes now, and they fall into certain groups. There are about four major categories. One of them is the sirtuins, which I work on. There are others. There's even a compound from Easter Island that seems to have also remarkable effects on anti-aging, on aging and extending lifespan in mice. So what we're all hoping to do, us researchers, is to develop ways to not really just extend lifespan but to keep people healthier for longer. We may just have a greater impact than a single drug because these drugs could potentially treat one disease but prevent 20 others.
[Ira Flatow:] And so you actually co-founded a company called Sirtris, which is now owned by GlaxoSmithKline, to come up to create these compounds, these anti-aging compounds?
[David Sinclair:] Well, it's true. A lot of scientists are hesitant to get involved with industry. It's seen as, you know, getting in bed with the devil, actually. But I found that doing this has been really the only way and one of the best ways I know to take a finding from the bench side to people. There's no other way, in fact. This drug, if we ever succeed, is going to cost probably a billion dollars, and no academic lab can do that. So yeah, I'm still working with, as a consultant to, GlaxoSmithKline. But they're the ones who have done the hard chemistry. They've made 4,000 different variants of chemicals that activate this pathway, and the best couple of those have gone into human studies.
[Ira Flatow:] So when you activate the pathway, this enzyme, what does what kind of benefits happen from that?
[David Sinclair:] Well, there are probably 1,000 papers now on this genetic pathway and the benefits of resveratrol. Not all the effects of resveratrol of course go through this one pathway. We think many of the important ones do. So for instance, we commonly see with these molecules that the animals are, as I mentioned, protected from the effects of obesity, so the lack of inflammation, their hearts are a bit stronger, their arteries are cleaner. They also seem to have improved brain function. They're protected against diseases like Alzheimer's. And they also seem to have more energy. We see that the mitochondria, these energy battery packs in our muscles and our liver, in fact in all of our cells, get revved up by these drugs. And this could be a way to give elderly people or sick people more energy and to fight disease, and possibly live longer.
[Ira Flatow:] Why not just drink a lot more red wine and get it that way?
[David Sinclair:] Well, I don't recommend people do that because the amount of resveratrol that's needed I estimate to be about 100 glasses a day, which is probably not recommended. So really what we're trying to do here is to develop drugs that could be taken as a little pill, maybe 250 milligram little pill, that could be used to treat diabetes but would also prevent cancer, Alzheimer's and inflammatory diseases. And yeah, I don't recommend people try to get resveratrol out of red wine, though I've been drinking red wine every few days because I know there are some health benefits, but definitely don't go overboard.
[Ira Flatow:] Could you do it with grape juice too?
[David Sinclair:] Well, actually, there's not much resveratrol in grape juice. Red wine has about a milligram or two per glass. But we're talking about hundreds of milligrams in these studies.
[Ira Flatow:] How is it that you get such a widespread benefit in all the different organs from just this one enzyme?
[David Sinclair:] That is the best question. What we think is going on is that well, let me back up. The old idea was that resveratrol and a lot of these compounds that seem to improve health work just because they're antioxidants. But it turns out resveratrol and red wine generally, it's not really a great antioxidant, and in fact it's been rather disappointing, the results for antioxidants in the aging field. So what we think is going on to have these, as you said, miraculous-like effects, is that these longevity genes, that there are many of these in our body, they get activated by adversity. So when we exercise, when we have a very low-calorie diet or even calorie-restrict, these pathways get activated, and they tell proteins in the cell to go off, say repair DNA better or turn on the energy supply more. And we think that those complex pathways downstream regulated by these master regulators of health are responsible.
[Ira Flatow:] And resveratrol is knows the pathway of how to do that, and these other drugs that you're developing basically do the same thing?
[David Sinclair:] Well, that's the theory. And in this paper that we just put out, what we're showing evidence for is that we're on target, that we are making drugs, and resveratrol as well, hits this enzyme in the cell that has these remarkable benefits, at least in animals so far.
[Ira Flatow:] So could you eventually market these as anti-aging drugs then?
[David Sinclair:] Well, if they worked, it would be great. I think proving that is going to take too long, I think, for most of us to wait. The way I think the first anti-aging drug will hit the market, and I don't know if it's going to be this work or someone behind us or even in front of us, there are a lot of people trying, but when it happens, and I think it will happen in our lifetimes, it'll be for a particular disease, because the drug approval process doesn't recognize aging as a disease. You couldn't get it on the market. But eventually I think if enough people take this medicine, let's say 10,000 people are on the drug, we would start to see even within a few years whether those people are generally healthier and possibly even longer lived than the general population.
[Ira Flatow:] And how soon will these trials start?
[David Sinclair:] Well, my colleagues roll their eyes whenever any of us gives an estimate. But I can say that we're in the companies are in phase one studies. Phase one studies means very small trials with, say, a dozen, up to 100 people. And the results so far have been promising, but they haven't proven anything. The timeframe forward typically from here on is about five years if things go well. But, you know, we have to be cautious because things can go wrong, and they often do in drug development. But, you know, we're certainly a lot closer than I ever thought we would be in my lifetime, and I certainly never thought that I'd be seeing patients given a drug that came out of the aging field so quickly.
[Ira Flatow:] Are there any bad side effects to this?
[David Sinclair:] Well, if you use really, really high doses of resveratrol, many grams, there can be some untoward side effects, some toxicity. So again, people shouldn't consider doing that. In the mouse studies, we haven't seen any signs of toxicity yet. We've been actually quite surprised. We've looked hard. We thought maybe there was a tradeoff, cancer would be invoked, or fertility would decline. We haven't seen any of that. And in these initial human studies that have recently been published with the synthetic compounds from that are in the clinical trials, they also, at least so far in small numbers of people, seem to be safe. But we need more people, of course. But there's nothing that I'm particularly worried about right now.
[Ira Flatow:] So in effect you basically slowed down the aging process in mice, or did you reverse it? Did you take away the aging process so they could live a lot, lot longer?
[David Sinclair:] Well, my colleagues and I debate whether we're really slowing down aging or we're just preventing diseases. That's probably going to be a debate we continue for a while. But in my lab, we are working on compounds that clearly do reverse aging or aspects of aging. We've got mice we haven't published this yet, but just as a heads-up, we've got compounds that can take a two-year-old mouse, which is a pretty old mouse, and reverse its metabolic aging within just a week. So I'm looking forward to not just delaying aging but even possibly reversing some of it.
[Ira Flatow:] Wow. Well, we'll talk about it some more. We've run out of time. David Sinclair, thank you very much for joining us.
[David Sinclair:] Hey, thanks for having me.
[Ira Flatow:] Dr. Sinclair is a professor in the Department of Genetic at Harvard Med School in Boston. We're going to take a break, and when we come back we're going to switch gears and take a closer look at bees bumblebees, honeybees, you name it, bee-autiful, coming after this break. Stay with us.