The Story of a Biologist & the Extension of the Human Life Span

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August 20, 2007

The Story of a Biologist & the Extension of the Human Life Span

Longevity Many have wished they could take a pill or drink a potion that could “magically” keep them young and healthy. David Sinclair, an anti-aging researcher and Harvard University professor of pathology, believes he is close to producing just such a remedy. (Abstract Chakra/Meridian hand print painting with the Chinese characters: "Health" and "Longevity").

The journey to find a proverbial fountain of youth has been years in the making for Sinclair. He famously discovered that the chemical resveratrol (a phytoalexin produced naturally by a variety of plants when under attack by bacteria or fungi) extends life span in mice by up to 24 percent and in other organisms by as much as 59 percent. Sinclair thinks that the compounds in resveratrol may be key in bumping up the human life span as well.

"The system at work in the mice and other organisms is evolutionarily very old, so I suspect that what works in mice will work in humans."

Sinclair believes that resveratrol works by activating SIRT1, a gene that is believed by many to play a fundamental role in controlling life span. Biologists have found that increasing the expression of SIRT1 slows aging and fends off age-related disease, including cancer and heart disease. If resveratrol can activate SIRT1, Sinclair may indeed have found a way to unlock the secret to a long, healthy life.

Sinclair is quite certain he’ll be successful and has found plenty of private investors who agree with him, but some of his peers have suggested that he doesn’t always look before he leaps. "David is brilliant, but sometimes he is too passionate and impatient for a scientist," says one colleague. "So far, he is fortunate that his claims have turned out to be mostly true."

Sinclair isn’t afraid of controversial research and isn’t too worried about what others think of him. He affectionately blames his unconventionality on his grandmother Vera, who fled to Australia in the wake of the failed 1956 revolution in her native Hungary.

"My grandmother is the black-sheep rebel of the family," he says. "She gave birth to my dad at age 15 in 1939--imagine the scandal then--and has lived with natives in New Guinea and eaten human flesh, among other things. She once got in trouble with the police for being the first person to wear a bikini on a Sydney beach. She's a '60s bohemian who helped raise me and taught me how to think differently and to question dogma."

Sinclair was attending the University of New South Wales and studying gene regulation in yeast when he learned about longevity research from Leonard Guarente, an MIT molecular biologist who was visiting Australia giving lectures. At the time (1993) most people assumed that aging was a complex and inevitable process that could not be regulated by just a few genes. But that same year, Cynthia Kenyon, a biologist at the University of California, San Francisco, published a study showing how manipulating a single gene, daf2, could double the life span of a tiny roundworm. Guarente himself was beginning experiments on yeast that would lead to the discovery of the anti-aging gene sir2 a couple years later.

Since the field of anti-aging was so new and unproven at the time, Guarente only talked about it informally—as he did when a young Australian scientist sat down next to him during lunch. "This was incredibly serendipitous," says Sinclair. Inspired by Guarente’s insights, he sold his Mazda Miata to buy a ticket to Boston to interview for a postdoc position in Guarente's lab. During his interview, he gave a spirited argument that the scientists studying aging should look for genes that prolong life rather than genes and mechanisms that end it. He was awarded the job.

While Sinclair was in Guarente's lab in the late 1990s, he discovered that sir2 prevents aging in yeast by slowing down the accumulation of ERCs, circular strands of DNA that build up in organisms as they age, eventually killing them.

But there was still the unsolved mystery of how to modulate genes, such as SIRT1, that regulate life span. Was there a compound that could be taken as a pill? Companies and labs began screening thousands of chemicals to see if one would work as a gene activator, but nothing turned out to be very promising.

Then in February 2003 in a small shoestring lab at Harvard, Sinclair was doing his own screening when he heard about a study suggesting that SIRT1 was activated by certain polyphenols, including resveratrol. Sinclair and Konrad Howitz, Biomol's director of molecular biology, collaborated to isolate resveratrol and test it in yeast and fruit flies. "Never in my wildest dreams did I think we would find an activator of sir2," says Sinclair.

Their research, along with other related studies, revealed that resveratrol-fed mice were healthier than the controls. Their cells were also aging remarkably slowly, even though the mice were being fed a fatty, unhealthy diet. Their research showed that mice on a high-fat diet fed large doses of resveratrol were as healthy as mice on a regular diet. Resveratrol also improved the mice's insulin sensitivity and increased their energy production. In effect, the mice stayed slender and strong regardless of a poor diet, while having energy-charged muscles and reduced heart rate of athletes. The number of mitochondria in their cells increased as well, which improved the cells' overall energy output.

This success in extending the life span and improving the health and vitality of mice partly assuaged critics who doubted resveratrol could extend life spans in mammals. But the critics are quick to point out that it still has to prove itself in human trials.

“Officially” Sirtris’ intention is not to produce drugs that extend life span (since that is not a goal recognized by the FDA), but the company has developed a supercharged version of resveratrol, called SRT501 to treat specific age-related diseases. It has also discovered novel small molecules that are not related to resveratrol that are supposedly a thousand times more potent in activating the sirtuins.

"This will impact humans within a decade," says Sinclair. "That's why I don't think there is anything more important than this quest. That's why I take chances, and why the controversy is worth it: because I think we are right."

Sinclair says his researchers are homing in on different sirtuin pathways and getting “great results”. Other than that, he says he can’t be more specific “on the record”.

The company has already started clinical trials in humans, and has another trial planned for later this year. Will this anti-aging visionary produce the promised results? Only time will tell, but if it does—there will be plenty of time to tell it.

Posted by Rebecca Sato

*This post was adapted from an article in MIT’s Technology Review

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How Resveratrol and Sirtuins work

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