How stem cells stay young

ADegeneration is inevitable for most cell types in the human body, but hematopoietic stem cells (HSCs) appear to defy this process. They maintain their self-renewal capacity almost throughout the lifespan of an organism and show a delayed onset of typical hallmarks of aging, such as DNA damage or protein aggregation. “Stem cells are really remarkable in terms of their longevity,” he says André Catica researcher studying aging at Baylor College of Medicine.

Previously, scientists discovered that one of the reasons that contributed to the longevity of HSC was that they could exist in a certain form functionally inactive state for extended periods.¹ Now Catic and his team have found another clue about how these cells maintain their youth. From a study recently published in Nature cell biologythey reported that HSCs contain high levels of the protein cyclophilin A, which prevents these cells from aging rapidly.² Understanding mechanisms of how HSCs avoid the wear and tear of aging has far-reaching implications, from figuring out the fundamental anti-aging secrets of cells to determining how breaking down these mechanisms could lead to leukemia.

Alzheimer’s disease and many other neurodegenerative disorders that occur as a result of age are caused by proteotoxic attacks.³ Here, the proteins become misfolded or clump together, and their accumulation begins to become difficult, Catic said.

‘The blood isn’t really one of the organs that causes us too many problems as we get older; Most people as they get older develop diseases like liver failure, neurodegenerative diseases and things like that,” he said. “There is no known Alzheimer’s in the blood, right?”

Curious about why that’s the case, Catic and his team isolated stem and progenitor cells from the bone marrow of mice to see if there was anything in their proteome. Because aging in other cells is caused by clumping of proteins, they combed the proteome looking for mechanisms that could cause less protein aggregation or clear out existing protein clumps.

This is how they encountered cyclophilin A, a chaperone that was highly expressed in these HSCs. The scientists found that older HSCs had lower levels of cyclophilin A, and that genetically removing it from young HSCs accelerated their aging. They also showed that reintroducing cyclophilin A to older HSCs rejuvenated them and improved their functions. All evidence pointed to this chaperone playing a key role in the lifespan of these stem cells.

“What’s interesting is that it’s not one of those chaperones that is active at the end of protein life,” Catic says. “Many chaperones help misfolded proteins, (they) refold them and bring them back into solution, or they are involved in their breakdown. Cyclophilin A is involved in the first step of protein synthesis.”

The team then further investigated cyclophilin A to better understand its role in translation. When they checked which types of proteins it bound to, they found that many RNA-binding proteins are involved in the assembly of ribosomes. Based on their findings, the scientists hypothesized that cyclophilin A was associated with ribosomes and concluded that it could help proteins fold as they emerge from the ribosome.

The team also found that this chaperone helped the synthesis of proteins intrinsically disordered regions (IDRs). These indeterminate structures within proteins are also called floppy domains. Because they do not have a very fixed structure, such proteins can adopt any desired conformation, according to Catic.

An advantage of this flexibility is that these proteins can have multiple binding partners; they can act as scaffolding proteins that can bring together other proteins, RNA and DNA to form complexes within the cell. “They make entire pathways come together, which is why we believe they are important for so many basic processes like splicing and translation,” says Catic.

Catic believes that these intrinsically disordered proteins may be involved in many important cellular functions that help keep stem cells healthy. Therefore, cyclophilin A, which promotes its translation, is useful for stem cell longevity.

Hartmut Geigera stem cell biologist at the University of Ulm who was not involved in the study was intrigued by the authors who investigated how proteins are regulated in aging stem cells. Geiger noted, “How can you get this nascent protein chain to come together and fold into a machine, especially the proteins with slack domains?”

“As far as I know, no one has looked into that, because this is a very complex infrastructure problem, right? How to really help make your most difficult-to-organize protein structures functional after they’ve been produced,” he added.

Along with cyclophilin A, Catic was quite stunned to find that the intrinsic disorder in the proteome was also reduced in older HSCs.

“Perhaps this could also have a protective effect, because intrinsically disrupted proteins, as important as they are, are also dangerous,” says Catic. “Because they like to bind to other proteins, they’re prone to aggregation, right? And if you look at neurodegenerative diseases, almost all of them are based on intrinsically disrupted proteins.”

“In Alzheimer’s disease or Huntington’s disease, for example, these disrupted proteins start to form aggregates that are so large that they cannot be cleared by the cell,” he explains.

Catic then wants to investigate the mechanisms by which IDR-rich proteins keep stem cells young. He also wants to delve deeper into the molecular details of what cyclophilin A does to a protein as it emerges from the ribosome, hoping to one day stimulate its expression in aging cells.

“Stem cell aging was previously defined mainly through scavenging mechanisms with chaperones,” he explained. “What we discovered is that protein translation is also very tightly regulated by cyclophilin A.”