Robert Signer sees himself as an auto mechanic for human cells. The professor of regenerative medicine at the University of California, San Diego, is fascinated by the elusive secrets of stem cells in our blood. This is a class of entities that regenerate red and white blood cells and platelets. Their job is to help keep our bodies healthy, but as we get older their performance declines. When they fail, this can lead to leukemia, anemia, clotting problems, and immune problems. Signer’s job is to understand why, and he believes the answer has something to do with how they handle their litter.
Our cells bring together about 20,000 specific proteins that allow us to do everything from digest dairy products to kill tumors. But the process is not perfect. When cells break down, what ends up is essentially junk: proteins with missing, extra, or incorrect amino acids in their chains. These can settle into unexpected shapes and glitches — or worse. “They’re starting to stick together, and they’re forming these clusters,” Sayner says. Gum builds up on the machine. The proteins can actually be unfolded toxic. (Researchers have linked Alzheimer’s disease to protein clumps.)
Most mature blood and immune cells live quickly and die hard. They thrive on producing 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 disastrous,” says Signer. If they get it wrong, waste leads to worse performance, which leads to more waste. So stem cells that are trying to survive for the long haul must manage their waste like a pro.
A healthy stem cell maintains tight control over protein production and breakdown, and it is this ability to maintain what researchers call “protein homeostasis” that wanes with age. “We think that if we can jump-start and prevent this from happening, or improve the ability of stem cells to maintain homeostasis of this protein, we might be able to prevent the decline in stem cell function and the diseases associated with these changes,” says Signer.
Biologists have long known that stem cells run a tight vessel, but not how. Even writing in the journal stem cell cells In March, Signer’s team reported a closer look at what’s going on inside the stem cells of young and old mice. (You can’t be a good mechanic if you never look under the hood, says Signer.)
What they learned was surprising. Biologists previously assumed that stem cells stay tidy by breaking down waste as quickly as they appear, reducing unwanted proteins into amino acid feed that can be immediately reused. But Signer’s team found that blood stem cells actually remove their own unfolded waste and recycle it only when it’s needed. Scientists have seen this behavior before, but they believed that cells do it only in rare cases, when they are under extreme stress. Signer now believes that healthy stem cells do this as a baseline – it’s a way of organizing themselves in order to maintain control. Mouse data showed that this complex process breaks down with age.
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 studied 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, she replaced old mice with more proteasomes, a move Signer likened to hitting 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.”
Why older stem cells change their behavior remains an open question. Florian suspects it has something to do with how cells change shape with age. Normally a healthy cell is asymmetric, with its contents divided into distinct sections – this asymmetrical shape is referred to as ‘polarized’. But stem cells lose their polarity with age, and this affects their ability to transport waste products to their storage centre.
Florian’s lab is developing drugs that maintain cell polarization. Last year, I reported regenerating mouse stem cells using a treatment that curbs the activity of an overactive enzyme that messes with cell polarity. When transplanted into immunocompromised mice, the stem cell treatment extended their average lifespan by more than 12 weeks, or 10 percent. “It has a very profound effect on the blood,” she says. “Essentially, you’re replenishing the mice’s blood, and they’ll be left healthy for longer.” (Florian serves on the advisory board for rejuvenation startup Mogling Bio.)
For his part, Signer envisions a drug that preserves the equipment stem cells use to create a fertilizer for denatured proteins—he doesn’t yet know what that would be, but the new experiment gives researchers an idea of where to look. Finding that the stem cell waste collection system breaks down as cells age, he says, because identifying what goes wrong with age gives us a clue as to how to target future repairs.
Signer and Florian acknowledge that any drug meant to keep cells young and active carries some cancer risk. Older cells activate tumor-suppressing genes And stem cell suppression. Helping stem cells survive into old age could help cancer cells do the same.
“But I also think there is an alternative possibility that it is happening in parallel,” says Signer. Perhaps stem cells can help slowly and steadily clean up their waste products It is forbidden The cascade of effects that lead to problems like cancer, he says: “If we can prevent some of these changes, we may be able to prevent multiple types of age-related diseases.”