Robert Signer sees himself as an auto mechanic for human cells. The professor of regenerative medicine at UC San Diego is intrigued by the elusive secrets of the stem cells in our blood. These are a class of rejuvenating entities that replenish supplies of red and white blood cells and platelets. Their job is to help keep our bodies healthy, but as we age their performance dips. When they fail, it can lead to blood cancers, anemia, clotting issues, and immune problems. Signer’s job is to understand why, and he thinks the answer has to do with how they handle their garbage.
Our cells assemble around 20,000 specific proteins that allow us to do everything from digesting dairy to killing tumors. But the process isn’t perfect. When cells mess up, they wind up with what’s essentially junk: proteins with missing, extra, or incorrect amino acids in their chains. These can settle into unexpected shapes and malfunction—or worse. “They start to stick together, and they form these aggregates,” Signer says. Aggregates gum up the machine. Misfolded proteins can actually be toxic. (Researchers have linked Alzheimer’s disease to gummed-up clumps of protein.)
Most mature blood and immune cells live fast and die hard. They thrive by churning out protein after protein, and mistakes are part of the deal. But life moves slowly for a stem cell. “Even modest increases in protein production can be very catastrophic,” says Signer. If they make a mistake, waste leads to worse performance, which leads to more waste. So stem cells trying to survive for the long haul must manage their waste like pros.
A healthy stem cell keeps tight control over protein’s production and destruction, and this ability to maintain what researchers call “protein homeostasis” is what fades with age. “We think that if we can jump in and prevent this from happening, or improve the ability of stem cells to maintain this protein homeostasis, then we might be able to prevent the decline in stem cell function and the diseases that are associated with those changes,” says Signer.
Biologists have long known that stem cells run a tight ship, but not how. So writing in the journal Cell Stem Cell in March, Signer’s team reported an up-close look at what happens inside the stem cells of young and old mice. (“You can't be a good mechanic if you've never looked under the hood,” Signer says.)
What they learned was surprising. Biologists had previously assumed that stem cells stay tidy by breaking down waste as fast as it arises, reducing junk proteins into amino acid fodder they can reuse immediately. But Signer’s group found that blood's stem cells actually squirrel away their misfolded waste and only recycle it when they need it. Scientists had seen this behavior before, but they thought that cells did it in rare cases, when under extreme stress. Signer now believes that healthy stem cells do this as a baseline—it’s a way of pacing themselves in order to maintain control. The mouse data showed that this sophisticated process breaks down with age.
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.”
Why older stem cells change their behavior remains an open question. Florian suspects it has something to do with how cells change shape as they age. A healthy cell is typically lopsided, as its contents are sectioned into distinct compartments—this asymmetric shape is referred to as being “polarized.” But stem cells lose their polarity with age, and this affects their ability to shuttle waste to their storage center.
Florian’s lab is developing drugs that maintain cell polarization. Last year, she reported rejuvenating mouse stem cells with a treatment that tamps down the activity of an overactive enzyme that messes with cell polarity. When transplanted into immunocompromised mice, the stem cell treatment extended their median lifespans by over 12 weeks, or 10 percent. “It has a very profound effect on the blood,” she says. “Basically, you rejuvenate the blood of the mice, and they leave healthier and longer.” (Florian serves on the advisory board for rejuvenation start-up Mogling Bio.)
For his part, Signer imagines a drug that maintains the equipment that stem cells use to compost malformed proteins—he doesn’t yet know what that would be, but the new experiment gives researchers an idea of where to look. Figuring out that stem cells’ trash collection system falls apart as the cells age is important, he says, because pinpointing what goes wrong with age gives us an idea of how to target future fixes.
Signer and Florian admit that any drug meant to keep cells young and active carries some cancer risk. Older cells activate genes that prevent tumors and suppress stem cells. It’s possible that helping stem cells survive in old age will help cancer cells do the same.
“But I also think that there is an alternative possibility happening in parallel,” Signer says. Maybe helping stem cells clear their trash slowly and steadily prevents the cascade of effects that lead to problems like cancer, he says: “If we can prevent some of those changes, we might be able to prevent multiple types of age-related diseases.”
