This revelation offers insight into why we age and what critical cellular machinery we must keep running to combat age-related diseases, according to Maria Carolina Florian, a stem cell biologist at the Catalan Institution for Research and Advanced Studies who was not involved in the work. To Florian, it suggests the possibility of creating drugs that can maintain this control for stem cells. It looks particularly important, she says, “because of this possibility to be targeted—to be able to reverse aging.”
Signer’s lab studied blood stem cells taken from mouse bone marrow. Doctoral researcher Bernadette Chua first extracted marrow from young mice (ages 6 to 12 weeks) and isolated several types of cells—stem cells as well as blood and immune cells—to observe them during an early stage of development. Then, using fluorescent molecules that stick to specific components of the cell, she snooped on each to see how it was managing its trash.
Cells use proteasomes, protein complexes containing enzymes that immediately chew up their misfolded proteins. But Signer’s lab had previously found that, like neural stem cells, blood stem cells in young mice don’t rely on proteasomes very much. In this new experiment, Chua and Signer found that instead of breaking down misfolded proteins right away, stem cells swept them out of the way, collecting them into piles, like mini junk yards. Later, they disintegrated them with a different protein complex called an aggresome. “We believe that by storing these misfolded proteins in one place, they’re basically holding onto those resources for when they need them,” Signer says. Collecting piles of waste may let cells control the pace of their recycling and, as a result, avoid living too fast or too slow.
Yet when Chua next examined marrow from 2-year-old mice, she found a shocking breakdown in this waste management system. Older mice lost their ability to form aggresomes almost entirely— at least 70 percent of the stem cells in young mice do it, but only 5 percent in old mice. Instead, old mice swapped to using more proteasomes, a move Signer likens to slapping a spare tire onto an aging car. “That was definitely a surprise,” Signer says.
This change in waste control machinery is bad news for stem cells. Mice that were genetically engineered to not cache their trash had four times fewer surviving stem cells in their bone marrow in old age. It suggests that those cells are aging, and expiring, faster than they were before.
This distinction between enzymes, wonky as it sounds, could prove crucial for efforts to harness stem cells as anti-aging therapies because it runs counter to previous assumptions. “Let’s say that you want to engineer a stem cell for regenerative medicine,” says Dan Jarosz, a systems biologist from Stanford University who was not involved in the work. “Before reading this, I might have thought that a really good thing to do would be to amp up the proteasome activity.”
The idea that young, healthy stem cells control the pace of their lives by collecting debris into a “storage center,” instead of consuming it immediately, “is very cool,” he continues. “This suggests that we need a much more nuanced understanding of how protein quality control functions in aging.”