“The usual caveats apply—it’s got to be reproduced by other people—but if it’s correct, without wanting to be too hyperbolic, it’s one of the more important aging discoveries ever,” says Norman Sharpless from the University of North Carolina at Chapel Hill School of Medicine, who was not involved in the study.
Several chemicals can slow the aging process in laboratory organisms, but Sharpless says it's hard to think how people might benefit. “You take a drug—resveratrol, green tea, god knows what—for 30 years, and by the time you’re 80, you’re actually 70. That paradigm doesn’t work in the real world. People hate to take drugs, especially when they don’t know it’s helping them. And no pharma company would develop such a drug. If this paper is right, suddenly you have a way of taking an old organism and making it physiologically younger. You go from a prevention paradigm to a treatment one. That's something you can sink your teeth into.”
Baker and van Deursen started this line of work by accident. In 2004, they found that turning off a gene called BubR1, which they initially thought would be involved in cancer, actually revved the aging process into high gear. The mice got cataracts, developed heart problems, lost body fat, and died much earlier than usual. And they seemed to accumulate many more senescent cells.
In 2011, the team developed a way of singling out and removing those cells. Senescent cells are characterized by a protein called p16. Baker and van Deursen genetically engineered their fast-aging mice so that they would destroy all their p16-bearing cells when they received a specific drug. The results were dramatic: The senescent cells disappeared, and though the rodents still died earlier, they were bigger, fitter, and healthier when they did. Even old mice, whose bodies had started to decline, showed improvements.
“Then, the question became: What would happen if we removed those cells in a normal mouse?” says Baker.
Using the same technique, Baker and van Deursen took normal middle-aged mice and purged their senescent cells twice a week. This time, the process increased the rodents’ average lifespan by a quarter. And as they got older, they lost less body fat, had healthier hearts and kidneys, developed fewer cataracts, and stayed more active. The team tested large numbers of mice of both sexes, from two genetic strains, and raised on two different diets—and the results were always the same. “This is a real improvement. It’s in real aging; the last paper was in fake aging,” says Sharpless.
John Sedivy from Brown University agrees. “This issue of whether senescent cells contribute to aging has been out there for decades,” he says. “This is the first paper that I’d say is really watertight.”
Senescent cells aren’t idle. They secrete molecules that trigger inflammation and enzymes that destroy connective tissue. “We've identified 50 to 60 different molecules that these cells produce, any one of which has the potential to wreak havoc on tissues,” says Judith Campisi from the Buck Institute for Research on Aging.