This revelation offers insight into why we age and what important cellular machinery we must continue to operate to combat age-related diseases, according to Maria Carolina Florian, a stem cell biologist at the Catalan Institute for Research and Advanced Studies who was not involved in the work. . For Florian, it suggests the possibility of creating drugs that can maintain this control in stem cells. It seems especially important, she says, “because of its potential to be targeted—the ability to reverse aging.”
Signer’s lab lesson Blood stem cells taken from mouse bone marrow. PhD researcher Bernadette Chua extracted marrow from young mice (6 to 12 weeks old) and isolated several types of cells — stem cells as well as blood and immune cells — to monitor them during an early stage of development. Then, using fluorescent molecules that stick to specific components of the cell, I snooped on each one to see how they managed their waste.
Cells use proteasomes, which are protein complexes that contain enzymes that immediately chew up unfolded proteins. But Signer’s lab previously found that, like neural stem cells, blood stem cells in young mice don’t depend on the proteasome so much. In this new experiment, Chua and Signer found that instead of immediately breaking down the denatured proteins, the stem cells kicked them out of the way, collecting them in piles, like little garbage yards. Later, they broke it down with a different protein complex called an aggresome. “We think that by storing these denatured proteins in one place, they are essentially conserving these resources for when they need them,” says Signer. Collecting waste mounds may allow cells to control the pace at which they are recycled and, as a result, to avoid living too fast or too slow.
However, when Chua then examined marrow from two-year-old mice, she found a shocking breakdown in this waste management system. Older mice have almost completely lost their ability to form aggregates—at least 70 percent of stem cells in young mice do so, but only 5 percent in old mice. Instead, the old mice replaced by using more proteasomes, a motion akin to slapping a spare tire on an old car. “It was definitely a surprise,” says Signer.
This change in waste control machinery is bad news for stem cells. Mice that had been genetically engineered not to store their own waste had four times fewer stem cells remaining in their bone marrow into old age. It indicates that these cells are aging and expiring faster than they used to be.
This distinction between enzymes, it appears, may be crucial for efforts to harness stem cells as anti-aging therapies because it runs counter to previous assumptions. “Let’s say you want to engineer a stem cell for regenerative medicine,” says Dan Jarrows, a systems biologist from Stanford University who was not involved in this work. “Before reading this, I probably thought that a really good thing would be increased protease activity.”
He adds that the idea that young, healthy stem cells control their pace of life by collecting debris into a “storage centre,” rather than immediately consuming it, is “pretty cool.” “This indicates that we need a more precise understanding of how protein quality control works in aging.”