The negative buzz about sirtuins recently grew louder when Science ran a lengthy news piece on Dec. 2 titled, “Aging Genes: The Sirtuin Story Unravels.” The article played up studies in lower organisms casting doubt on earlier high-profile reports that sirtuin enzmes play major roles in aging, which in turn challenged the idea that they mediate health benefits linked to resveratrol, the famed red-wine ingredient. The most glaring of the skeptical reports, a British-led study that appeared in September in Nature, contradicted earlier studies that showed amping up a sirtuin called Sir2 in roundworms and fruit flies extends their lifespans. In the Science article, Linda Partridge, one of the British researchers, was quoted as saying that her team’s study “‘is basically a boring little story that says if you do the experiments properly,’ you arrive at the correct results.” This is pretty strong acid, no?
Partridge, along with editors of Science, apparently see the sirtuin story as an overfilled balloon begging to be popped. Joining in the fun, Nature‘s editors recently ran a headline—”Don’t write off sirtuins”—implying that they’re now in danger of being placed in the same category as a deadbeat’s IOU. But thanks to all the gleeful popping, we’re faced with a strange situation: The studies in yeast, worms and flies have totally upstaged a large, growing body of encouraging findings on sirtuins and resveratrol in mammals, including several small but revealing human clinical studies that recently appeared with little or no media notice. This situation is a first as far as I know when it comes to coverage of an important biomedical topic.
Don’t get me wrong: The studies in lower organisms have shed intriguing light on sirtuins and helped dispel simplistic views on how they work. But to my admittedly mammalian eyes, the recent heavy emphasis on them leaves something to be desired. If you happen to be warm-blooded, what follows are a few intriguing findings on sirtuins that you may have missed while reading about how the story on them has unraveled. (If you’re a fly or worm, just skip it.)
–In an Australian study of 19 overweight and obese people with borderline high blood pressure, taking single doses of dietary supplements containing 30 to 270 milligrams of resveratrol (the brand name was resVida) was found to yield a statistically significant improvement in a measure of cardiovascular health called flow-mediated dilatation of the brachial artery, or FMD, one hour after the doses were taken. (FMD is is a widely-used measure to assess heart-disease risk.) Importantly, the researchers showed that the higher the resveratrol dose, the greater the improvement—such dose-dependency suggested that the observed improvements weren’t flukes, and that they were due to the resveratrol doses. The study was funded by resVida’s maker, Switzerland’s DSM Nutritional Products.
–A double-blind, randomized study of 19 patients with type 2 diabetes showed that taking 10 milligrams a day of resveratrol supplements for four weeks induced a statistically significant drop in blood glucose after meals and a lessening of other signs of insulin resistance (the hallmark symptom of diabetes). That daily dose was not much more than moderate wine drinkers get—some red wines contain 1 to 2 milligrams per glass. (The idea that a person would have to knock back whole cases of wine to get significant health benefits from resveratrol, suggested by 2006 mouse studies in which the animals were given huge doses, now appears to have been wrong.) The Hungarian researchers who led the study at University of Pécs suggested that resveratrol’s ability to reduce oxidative stress (the kind of damage caused by free radicals) might underlie the benefits they saw.
–A double-blind, randomized trial of 11 obese males who took 150-milligram resveratrol supplements for 30 days (resVida, whose maker helped to fund the study) showed that men experienced a number beneficial metabolic changes resembling those seen in mice on much higher doses. While “modest,” the changes—including lower systolic blood pressure, signs of reduced body-wide inflammation, and enhanced energy metabolism leading to reduced fat deposits—suggested that surprisingly small doses of resveratrol can rapidly induce beneficial effects resembling those of calorie restriction or endurance training. The study also presented evidence that the metabolic changes were mediated by an enzyme called AMPK, which in turn revved up SIRT1, a sirtuin that many studies have implicated in mammalian aging and calorie restriction.
This latter study made the cover of Cell Metabolism, a prominent journal. But it garnered little media attention, despite the fact that its blood-pressure finding alone was arguably quite important. Briefly, the researchers showed that taking the smallish doses of resveratrol supplements for a month yielded a statistically significant reduction in systolic blood pressure (the P value was 0.006, indicative of a robust result despite the small number of subjects)—it dropped from 130.5 on placebo to 124.7 on resveratrol (we’re talking millimeters of mercury, of course). The finding was consistent with a growing body of evidence that boosting SIRT1 can lower blood pressure—see here for a recent example. The 5.8 mm reduction in systolic pressure may sound small. But it has become increasingly clear in the cardiac literature that even small reductions in blood pressure can have major effects on disease risks as people age. As an important 2006 study showed, adults with “high normal” blood pressure, defined as having systolic readings between 130 and 139, have more than twice the risk of cardiovascular disease as people with readings below 120.
With the exception of the Dutch study, the recent human studies on resveratrol didn’t shed much light on whether the chemical works by activating SIRT1. That issue is hotly debated, with sirtuin skeptics asserting that resveratrol’s calorie-restriction-like effects have nothing to do with SIRT1, while others, most notably David Sinclair at the Harvard Medical School, contending that its effects are largely channeled through SIRT1. Perhaps of most interest to warm-blooded readers, a number of mammalian studies on resveratrol’s effects have suggested SIRT1 is a key channel through which the substance can improve cardiovascular health. (For some examples, see here, here and here.)
A recently reported mouse study at the National Institute on Aging also lent support to the idea that amping up SIRT1 in mammals on overly rich diets can help avert the diets’ hurtful effects in a way that resembles what calorie restriction (CR) does. (It should be noted, though, that resveratrol has failed to extend the lifespans of normally-fed mice in earlier studies, suggesting that, at most, it only partly mimics CR’s effects in mammals.) The study, overseen by the institute’s Rafael de Cabo, looked at the effects of SRT1720, a drug developed by Sirtris Pharmaceuticals, a biotech cofounded by Sinclair and now a part of GlaxoSmithKline, to stimulate SIRT1 more potently than resveratrol does.
SRT1720 may ring a bell—sirtuin skeptics are fond of trotting out a Pfizer study last year suggesting that the drug doesn’t really stimulate SIRT1 and, worse, is actually toxic to mice. The toxicity finding was based on the administration of SRT1720 to 8 mice for 18 days. In the national institute’s study, an equivalent daily dose was given to over 100 mice for more than 80 weeks while they given fattening food; not only did the animals show no signs of toxicity, but they lived, on average, up to 44% longer than similarly fed mice that didn’t get the drug—not surprising, given the study’s other data indicating that the drug fended off deleterious effects of their overly rich diets. Indeed, the reduction of liver fat in the SRT1720-treated mice was so pronounced that it was “apparent even to the naked eye” in tissue samples, their increased longevity (of both maximum and mean lifespan) was dose-dependent (more resveratrol yielded bigger gains), the drug suppressed inflammation-associated changes in the rodents’ livers and hearts, it improved their insulin sensitivity, and it caused gene-activity changes resembling those induced by both resveratrol and calorie restriction. Call me a prejudiced Eutherian if you like, but I find this rigorous, long-term mouse study, which is consistent with several others on SRT1720, more compelling than Pfizer team’s brief look at the drug.
While the national institute’s study didn’t conclusively show that SRT1720 acts via SIRT1, the researchers found that telltale changes induced by the drug in liver-cell mitochondria, tiny power plants in cells, didn’t occur in mice with disabled SIRT1 genes—evidence that the sirtuin enzyme is a major conduit of the drug’s action. Similarly, a number of other studies involving bioengineered mice with SIRT1-disabled and SIRT1-enhanced genes have suggested that boosting SIRT1 helps ward off diabetes and other diseases brought on by aging and obesity. A good review on these data can be found here.
All these mammalian results on sirtuins, resveratrol and sirtuin-targeting drugs don’t prove that the earlier, over-the-top excitement about them was warranted. Perhaps the strongest conclusion that an unbiased observer could draw at this point from all the data on sirtuins is that their activity depends very much on the context in which it is observed. Importantly, however, the context of greatest interest for most of us aging mammals is aging mammals, where boosting sirtuin activity appears to do really nice things in certain organ systems. And if I were an obese mammal with hypertension, I’d be sorely tempted at this point to try taking modest daily doses of a resveratrol supplement for a month to see whether it brings down my blood pressure. While I wouldn’t expect such an experiment to make me live a lot longer, I think I could justifiably entertain the hope that it just might help me age more gracefully.
Sirtuin News For Mammals
The negative buzz about sirtuins recently grew louder when Science ran a lengthy news piece on Dec. 2 titled, “Aging Genes: The Sirtuin Story Unravels.” The article played up studies in lower organisms casting doubt on earlier high-profile reports that sirtuin enzmes play major roles in aging, which in turn challenged the idea that they mediate health benefits linked to resveratrol, the famed red-wine ingredient. The most glaring of the skeptical reports, a British-led study that appeared in September in Nature, contradicted earlier studies that showed amping up a sirtuin called Sir2 in roundworms and fruit flies extends their lifespans. In the Science article, Linda Partridge, one of the British researchers, was quoted as saying that her team’s study “‘is basically a boring little story that says if you do the experiments properly,’ you arrive at the correct results.” This is pretty strong acid, no?
Partridge, along with editors of Science, apparently see the sirtuin story as an overfilled balloon begging to be popped. Joining in the fun, Nature‘s editors recently ran a headline—”Don’t write off sirtuins”—implying that they’re now in danger of being placed in the same category as a deadbeat’s IOU. But thanks to all the gleeful popping, we’re faced with a strange situation: The studies in yeast, worms and flies have totally upstaged a large, growing body of encouraging findings on sirtuins and resveratrol in mammals, including several small but revealing human clinical studies that recently appeared with little or no media notice. This situation is a first as far as I know when it comes to coverage of an important biomedical topic.
Don’t get me wrong: The studies in lower organisms have shed intriguing light on sirtuins and helped dispel simplistic views on how they work. But to my admittedly mammalian eyes, the recent heavy emphasis on them leaves something to be desired. If you happen to be warm-blooded, what follows are a few intriguing findings on sirtuins that you may have missed while reading about how the story on them has unraveled. (If you’re a fly or worm, just skip it.)
–In an Australian study of 19 overweight and obese people with borderline high blood pressure, taking single doses of dietary supplements containing 30 to 270 milligrams of resveratrol (the brand name was resVida) was found to yield a statistically significant improvement in a measure of cardiovascular health called flow-mediated dilatation of the brachial artery, or FMD, one hour after the doses were taken. (FMD is is a widely-used measure to assess heart-disease risk.) Importantly, the researchers showed that the higher the resveratrol dose, the greater the improvement—such dose-dependency suggested that the observed improvements weren’t flukes, and that they were due to the resveratrol doses. The study was funded by resVida’s maker, Switzerland’s DSM Nutritional Products.
–A double-blind, randomized study of 19 patients with type 2 diabetes showed that taking 10 milligrams a day of resveratrol supplements for four weeks induced a statistically significant drop in blood glucose after meals and a lessening of other signs of insulin resistance (the hallmark symptom of diabetes). That daily dose was not much more than moderate wine drinkers get—some red wines contain 1 to 2 milligrams per glass. (The idea that a person would have to knock back whole cases of wine to get significant health benefits from resveratrol, suggested by 2006 mouse studies in which the animals were given huge doses, now appears to have been wrong.) The Hungarian researchers who led the study at University of Pécs suggested that resveratrol’s ability to reduce oxidative stress (the kind of damage caused by free radicals) might underlie the benefits they saw.
–A double-blind, randomized trial of 11 obese males who took 150-milligram resveratrol supplements for 30 days (resVida, whose maker helped to fund the study) showed that men experienced a number beneficial metabolic changes resembling those seen in mice on much higher doses. While “modest,” the changes—including lower systolic blood pressure, signs of reduced body-wide inflammation, and enhanced energy metabolism leading to reduced fat deposits—suggested that surprisingly small doses of resveratrol can rapidly induce beneficial effects resembling those of calorie restriction or endurance training. The study also presented evidence that the metabolic changes were mediated by an enzyme called AMPK, which in turn revved up SIRT1, a sirtuin that many studies have implicated in mammalian aging and calorie restriction.
This latter study made the cover of Cell Metabolism, a prominent journal. But it garnered little media attention, despite the fact that its blood-pressure finding alone was arguably quite important. Briefly, the researchers showed that taking the smallish doses of resveratrol supplements for a month yielded a statistically significant reduction in systolic blood pressure (the P value was 0.006, indicative of a robust result despite the small number of subjects)—it dropped from 130.5 on placebo to 124.7 on resveratrol (we’re talking millimeters of mercury, of course). The finding was consistent with a growing body of evidence that boosting SIRT1 can lower blood pressure—see here for a recent example. The 5.8 mm reduction in systolic pressure may sound small. But it has become increasingly clear in the cardiac literature that even small reductions in blood pressure can have major effects on disease risks as people age. As an important 2006 study showed, adults with “high normal” blood pressure, defined as having systolic readings between 130 and 139, have more than twice the risk of cardiovascular disease as people with readings below 120.
With the exception of the Dutch study, the recent human studies on resveratrol didn’t shed much light on whether the chemical works by activating SIRT1. That issue is hotly debated, with sirtuin skeptics asserting that resveratrol’s calorie-restriction-like effects have nothing to do with SIRT1, while others, most notably David Sinclair at the Harvard Medical School, contending that its effects are largely channeled through SIRT1. Perhaps of most interest to warm-blooded readers, a number of mammalian studies on resveratrol’s effects have suggested SIRT1 is a key channel through which the substance can improve cardiovascular health. (For some examples, see here, here and here.)
A recently reported mouse study at the National Institute on Aging also lent support to the idea that amping up SIRT1 in mammals on overly rich diets can help avert the diets’ hurtful effects in a way that resembles what calorie restriction (CR) does. (It should be noted, though, that resveratrol has failed to extend the lifespans of normally-fed mice in earlier studies, suggesting that, at most, it only partly mimics CR’s effects in mammals.) The study, overseen by the institute’s Rafael de Cabo, looked at the effects of SRT1720, a drug developed by Sirtris Pharmaceuticals, a biotech cofounded by Sinclair and now a part of GlaxoSmithKline, to stimulate SIRT1 more potently than resveratrol does.
SRT1720 may ring a bell—sirtuin skeptics are fond of trotting out a Pfizer study last year suggesting that the drug doesn’t really stimulate SIRT1 and, worse, is actually toxic to mice. The toxicity finding was based on the administration of SRT1720 to 8 mice for 18 days. In the national institute’s study, an equivalent daily dose was given to over 100 mice for more than 80 weeks while they given fattening food; not only did the animals show no signs of toxicity, but they lived, on average, up to 44% longer than similarly fed mice that didn’t get the drug—not surprising, given the study’s other data indicating that the drug fended off deleterious effects of their overly rich diets. Indeed, the reduction of liver fat in the SRT1720-treated mice was so pronounced that it was “apparent even to the naked eye” in tissue samples, their increased longevity (of both maximum and mean lifespan) was dose-dependent (more resveratrol yielded bigger gains), the drug suppressed inflammation-associated changes in the rodents’ livers and hearts, it improved their insulin sensitivity, and it caused gene-activity changes resembling those induced by both resveratrol and calorie restriction. Call me a prejudiced Eutherian if you like, but I find this rigorous, long-term mouse study, which is consistent with several others on SRT1720, more compelling than Pfizer team’s brief look at the drug.
While the national institute’s study didn’t conclusively show that SRT1720 acts via SIRT1, the researchers found that telltale changes induced by the drug in liver-cell mitochondria, tiny power plants in cells, didn’t occur in mice with disabled SIRT1 genes—evidence that the sirtuin enzyme is a major conduit of the drug’s action. Similarly, a number of other studies involving bioengineered mice with SIRT1-disabled and SIRT1-enhanced genes have suggested that boosting SIRT1 helps ward off diabetes and other diseases brought on by aging and obesity. A good review on these data can be found here.
All these mammalian results on sirtuins, resveratrol and sirtuin-targeting drugs don’t prove that the earlier, over-the-top excitement about them was warranted. Perhaps the strongest conclusion that an unbiased observer could draw at this point from all the data on sirtuins is that their activity depends very much on the context in which it is observed. Importantly, however, the context of greatest interest for most of us aging mammals is aging mammals, where boosting sirtuin activity appears to do really nice things in certain organ systems. And if I were an obese mammal with hypertension, I’d be sorely tempted at this point to try taking modest daily doses of a resveratrol supplement for a month to see whether it brings down my blood pressure. While I wouldn’t expect such an experiment to make me live a lot longer, I think I could justifiably entertain the hope that it just might help me age more gracefully.