So You Want to Live Forever?
by David Ewing Duncan Nov 7 2007
Sirtris Pharmaceuticals is testing a fountain-of-youth pill in humans. You won’t live forever, but it may slow aging and increase lifespan. So far, it’s working.
When Spanish explorer Juan Ponce de Leon heard rumors of a fountain of youth from native Floridians in 1513, he was desperate enough to find it that he was willing to march in chain mail through fetid swamps infested with mosquitoes, alligators, and hostile locals. He never found it.
Nearly five centuries later, the fabled longevity imbued by Florida’s mythic fountains may be here for real. Not spewing from a magical spring with sweet-tasting waters, but in a pill designated SRT501.
In Cambridge, Massachusetts, Sirtris Pharmaceuticals is testing such a pill in humans in a Food and Drug Administration-approved clinical trial. The tests began last spring with 85 volunteers; in August, the company announced that this medication designed to slow aging and bump up lifespan is working.
A caveat: It will take years of tests and trials to know if the drug will ultimately permit people to routinely live to over 100 years old, while fending off diseases of aging ranging from diabetes to cancer.
You may remember hearing about the seemingly miraculous chemical that SRT501 is based on, called resveratrol. Sirtris co-founder and Harvard professor David Sinclair created a sensation when he announced in 2003 that this naturally occurring compound extends the lifespan of yeast.
This might not have attracted much notice except that resveratrol is found in one of the most popular beverages in the world - red wine - a drink associated with rejuvenation even in the days of Ponce de Leon. According to Sinclair, the grape skins contain the substance, which is passed on during the winemaking process to vins rouges ranging from the humblest Gallo jug wine to the finest St. Emilion.
SRT501 impacts a family of genes in humans and other organisms called “sirtuins,” which seem to control a cornucopia of desirable functions in cells that lead to improvements in diseases ranging from obesity and diabetes to Alzheimer’s and cancer.
Sinclair and other scientists at Sirtris and Harvard announced in September that they had discovered mechanisms in mice explaining how two sirtuin genes - there are seven in humans and mice - activate cell defenses that lead to extended lifespan in mice.
Sirtris also is assembling what amounts to a small but burgeoning anti-aging empire as they snap up intellectual property and amass a war chest of cash that includes a $62 million initial share offering last May, added to $103 million raised in private rounds since the company was founded in 2004.
The other co-founder is serial entrepreneur and venture capitalist Christoph Westphal. Before starting Sirtris, he had been a co-founder of two successful biotech firms, Alnylam Pharmaceuticals and Momenta Pharmaceuticals.
Sirtris recently said it would license a patent from the Massachusetts Institute of Technology that covers the actions of a gene that can slow atherosclerosis - hardening of the arteries that can lead to heart attack and stroke - and other age-related diseases.
The patent comes from the lab of Leonard Guarente, who was Sinclair’s mentor at the Massachusetts Institute of Technology and the discoverer of sirtuin’s life-extending properties.
Guarente is co-founder of Sirtris’s major competitor, Elixir Pharmaceuticals, also based in Cambridge. Founded in 1999, Elixir owns its own intellectual property related to SIRT genes and other age-slowing processes, but their compounds to activate SIRT have yet to be tested in humans.
Other drugs developed by the company are entering final-stage human testing (Phase III trials) for Type 2 diabetes. Last year, Guarente left Elixir and has expressed an interest in joining Sirtris after a one-year non-compete clause ends late this year.
In 2005, Sinclair again made headlines when he published a paper in the scientific journal Nature detailing how mice on a high-fat diet were fed massive doses of resveratrol stayed as healthy as mice on a regular diet.
Resveratrol also sharply extended lifespan, produced positive changes in insulin sensitivity and other diabetes-preventing mechanisms, and increased energy production in cells.
The mice were fed very high doses of resveratrol - 22 milligrams per kilogram of weight. In comparison, a liter of red wine delivers 1.5 to 3 milligrams. To match the results in the mice a 150-pound human would need to drink 750 to 1,500 bottles of wine a day.
Sinclair says that SRT501 is 1,000 times more potent than naturally occurring resveratrol, which gives it the same punch as the resveratrol in all of those bottles of wine.
Because humans are so long-lived, SRT501 cannot be easily tested for longevity in humans, nor does the Food and Drug Administration recognize “increased lifespan” as an allowable indication for an approved drug.
This is why the company is testing SRT501 for diseases related to aging, such as Type 2 diabetes. However, should the drug be approved for diabetes, it will undoubtedly be used by many people without diabetes to extend lifespan.
The drug still has years of testing to go and faces many hurdles. It may not work. But if it does, the consequences will be profound.
It could, for instance, mean Earth’s population could grow faster as death rates fall. Age 90 will be the new 70, and 70 the new 50, with dramatic impacts on everything from the Social Security system and other pension programs to what is a reasonable new retirement age. It may also mean fewer people with diabetes, Alzheimer’s, and some cancers.
Can one pill do and cause all of that? Critics have long said no - such a compound would not work in humans. But they also said it wouldn’t work in mice - until it did work, at least in fat mice.