Clearing the Body's Retired Cells Slows Aging and Extends Life

A series of experiments in mice has led to what some are calling “one of the more important aging discoveries ever."

I'm looking at a picture of two mice. The one on the right looks healthy. The one on the left has graying fur, a hunched back, and an eye that's been whitened by cataracts. “People ask: What the hell did you do to the mouse on the left?” says Nathaniel David. “We didn't do anything.” Time did that. The left mouse is just old. The one on the right was born at the same time and is genetically identical. It looks spry because scientists have been subjecting it to an unusual treatment: For several months, they cleared retired cells from its body.

Throughout our lives, our cells accumulate damage in their DNA, which could potentially turn them into tumors. Some successfully fix the damage, while others self-destruct. The third option is to retire—to stop growing or dividing, and enter a state called senescence. These senescent cells accumulate as we get older, and they have been implicated in the health problems that accompany the aging process.

By clearing these senescent cells from mice, Darren Baker and Jan van Deursen at the Mayo Clinic College of Medicine managed to slow the deterioration of kidneys, hearts, and fat tissue. The animals lived healthier and, in some cases, they lived longer.

“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.

“Without wanting to be too hyperbolic, it’s one of the more important aging discoveries ever.”

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.

This seems perverse, but there’s method to the body’s madness. Cells undergo senescence because they accumulate damage that could potentially lead to cancer, and the molecules they secrete prompt the immune system to come over and clear them. “It’s a very potent anti-cancer mechanism,” says Baker. But as we get older, the immune system falters, and senescent cells accumulate. Now, the molecules they secrete become problems rather than solutions.

Even then, senescent cells have benefits. Last year, Campisi showed that these cells help to heal wounds. And sure enough, Baker and van Deursen found that their mice heal more slowly after such cells were removed.

The worry then is that any attempt to clear senescent cells in people would have serious side effects, as well as obvious benefits. Charles Sherr from St. Jude Children's Research Hospital is also concerned about cancer. Since the p16 protein prevents tumors from arising, Sherr wonders if “the salutary effects that accompany elimination of p16+ cells would be offset later by increased cancer incidence.” Baker and van Deursen saw no signs of that in their mice, but humans live for much longer than rodents.

“There will be tradeoffs for sure, but as we drill down into the biology, we have a better chance of preserving the good side of these cells while eliminating the bad,” says Campisi.

A newly launched company called Unity Biotechnology, which counts Campisi and van Deursen among its co-founders, is working to move the team’s senescence-clearing discoveries to the clinic. “We have spent the last four years identifying a series of Achilles heels that are unique to senescent cells,” says Unity CEO Nathaniel David. “We have molecules that are 300 times more poisonous to these cells than to non-senescent ones.”

His first goal is to use these compounds to treat a couple of diseases that are likely caused by senescent cells and that are localized to specific body parts. Osteoarthritis might be a good target—David has it in his toes—and so might late-stage glaucoma. If that works, “we can start going after higher-risk stuff like healthspan,” says David.

http://www.theatlantic.com/science/archive/2016/02/clearing-retired-cells-extends-life/459723/