Sensing the onset of advancing age, many people - usually on doctor's advice - take to popping a baby aspirin tablet (81 milligrams) daily. The rationale is that it wards off looming atherosclerosis and accompanying cardiovascular diseases.
Of late, some health-conscious circles have added red wine - vino tinto - to their quotidian diet, on the rumor that a glass or two of red wine also can forfend heart and stroke attacks among the aging.
"Red wine is associated with a surprising number of health benefits," observed molecular geneticist David Sinclair at Harvard University. "Most notably," he added, "the mitigation of age-related diseases, including neurodegeneration, carcinogenesis and atherosclerosis."
Sinclair equates the virtue of red wine to the weight-abating blessing of calorie restriction. To investigate this pro-slimming effect, he turned to Saccharomyces cerevisiae - baker's yeast. "We focused on a prime molecular ingredient of red wine, resveratrol by name," he said. It was discovered by a Nature paper's lead author, Konrad Howitz, director of molecular biology at BIOMOL Research Laboratories Inc. in Plymouth Meeting, Pa. "Glucose restriction, a form of calorie restriction in yeast, resulted in no significant extension of long-lived, resveratrol-treated cells, indicating that resveratrol probably acts through the same pathway as calorie restriction."
Reaching back in history, Sinclair recounted, "In 1935 a fellow called Clive McKay found that restricting calories to rats made them live significantly longer. And in those animals it also prevented the diseases of old age, such as cancer, heart disease and osteoporosis." (See BioWorld Today, Sept. 14, 2003.)
Keys: Resveratrol, Sirtuin, Acetylase
"So since then," Sinclair continued, "scientists have dreamed of one day finding small molecules that could mimic this effect. But it's always been in the realm of science fiction. In the past 10 years, a number of labs, including my own, have made great strides in identifying the genes that regulate life span in model organisms - even mice."
Sinclair is senior author of an article in Nature dated Aug. 24, 2003. Its title: "Small molecule activators of sirtuins extend Saccharomyces cerevisiae life span."
"Our message," he told BioWorld Today, "is that it's possible to find small molecules that activate longevity regulators, like sirtuin. And if that's possible, it brings into the realms of possibility that one day we will be able to find small molecules that can manipulate life span. We'll be able to alter life expectancy by preventing diseases of old age.
"I would go so far as to say that this is a breakthrough in the field," Sinclair ventured. "The reason I say that is there are a lot of stories in the media about aging. But the big difference is that until now scientists have been changing the life spans of organisms through genetic means. Of course we cannot apply that directly to humans; there's no way we can genetically engineer people. So what we've got here is the first real indication that we'll be able to have the same effect. And if they're safe to use we should be able to drug those molecules into therapeutic compounds.
"The next big step, I believe, has been made. We can now design molecules that alter this longevity pathway in animals. So if we're right about this, we may have drugs that one day can produce the same health benefits of calorie restriction.
"Resveratrol is the molecule that came from Howitz's screening trying to understand why red wine is good for human health," Sinclair went on. "There are reports about the French having a longer life because of their drinking red wine. In general, red wine has been linked to cardio-protection and even suppression of cancer in animal models. It turns out that the active ingredient is resveratrol.
"It's always been thought," he continued, "that molecules like resveratrol are chemical polyphenols. That their major activity in providing major health benefits is through their antioxidant activity. What we're saying is that maybe that's the most important thing they do. Maybe it's not because they activate the sirtuin longevity pathway in animals. That would mean these molecules are turning on an active cellular defense response that protects the cells against damage coming in from the environment - and also free radicals that are generated inside cells themselves.
"This is more of an active defense response rather than something relatively passive like a chemical reaction. We don't know yet how polyphenol works to activate sirtuin, but we're trying to understand that so we can design better synthetic molecules than the natural ones we found."
The next tool in Sinclair's kit is acetylation. "It's a recently discovered chemical modification that cells make on proteins to control them," he explained. "Sirtuin removes acetyl groups from proteins," Sinclair went on. "I don't know for sure yet what relevance this has to humans. Our only clue is that sirtuin's SRT1 molecule does seem to regulate the p53 tumor suppressor. What we showed in Nature is that it can delay cell death; buy cells a little bit of time to try to repair themselves before they head down a suicide pathway."
Drink Red Wine, Yes or No?
"Since submitting the Nature paper," Sinclair observed, "we've made a number of new discoveries. They include preliminary evidence that these molecules work on higher organisms, such as fruit flies and nematodes."
Asked if people should drink red wine - following the same regimen as baby aspirin - Sinclair demurred: "I'm not a doctor so I may get into trouble if I started recommending dietary changes. But it's almost unavoidable, when you hear these stories from the media, not to start drinking a little bit more red wine than you did previously.
"We've made another breakthrough that's not in the journal paper. Our goal is to improve on resveratrol and these other molecules because they are not very stable. They oxidize very rapidly in the air. So we're well under way in designing improvements of synthetic derivatives of resveratrol and these other molecules that we've found. We're already at the stage of testing them in animals. We work our way up the evolutionary ladder, starting with yeast. Then we go to round worms and fruit flies. If they work, we move into mice. But even with resveratrol we're already in the planning stages to test it in mice, hopefully some time early next year. Anyway," he concluded, "that's the plan."
"We filed a provisional patent application jointly by BIOMOL and Harvard," Howitz said. "It covers use of these molecules for claiming sirtuin-activating compounds with the aim of various clinical benefits that may come out of it."