UIC researchers discover an important cellular mechanism that drives aging

As our hairs go gray and our muscles weaken with age, our immune system also changes. In particular, the stem cells that become blood or immune cells can develop mutations, potentially leading to cancers or other dysfunctions.

Researchers at the University of Illinois Chicago have discovered an important cellular mechanism that drives this aging: the lack of a protein called platelet factor 4, whose levels decrease with age, they report in the journal Blood. What's more, adding this protein to old blood cells reversed these signs of aging, which points to a promising therapeutic target for preventing or improving age-related disorders in the blood and immune systems.

Hematopoietic stem cells, also known as blood stem cells, are a special type of cell that live in the bone marrow and can develop into the ever-important blood and immune cells.

Our hematopoietic stem cells are very rare. We call them the Holy Grail of the immune system."

Sandra Pinho, associate professor of pharmacology and regenerative medicine, College of Medicine, UIC

In a young body, hematopoietic stem cells can easily generate both major groups of blood cells: myeloid cells, which include some immune cells as well as red blood cells that transport oxygen, or lymphoid cells, which include the T and B cells that protect us from infections.

But as the body ages, the hematopoietic stem cells are more inclined to become myeloid cells and make fewer and fewer lymphoid cells. This, in turn, changes how aging peoples' immune systems act. "That's one of the reasons why, normally, older individuals are not used as donors for bone marrow transplantation, because their stem cells are not as potent," Pinho said.

In mice and in human bone marrow samples, Pinho and her colleagues discovered that platelet factor 4 is heavily involved in this aging process. In young mice and people, platelet factor 4 acts as a messenger, telling hematopoietic stem cells, especially the ones that generate myeloid cells, to stop multiplying and preventing them from proliferating out of control. With age, the immune cells produce less platelet factor 4, allowing them to proliferate.

"When stem cells start to divide more often than they should, and if their proliferation is not regulated, they can accumulate mutations over time," said Pinho. In humans, these mutations can lead to inflammation, increase the risk of blood cancers, and even contribute to cardiovascular disease.

But incredibly, the scientists found that supplying platelet factor 4 to older mice undid signs of aging in their hematopoietic stem cells. They gave the animals a blood infusion of platelet factor 4 every day for over a month and found that their immune and blood cells appeared and acted much younger.

The same was true when the researchers added the protein to older human stem cells in experiments in the lab. "It rejuvenated the aging of the blood system," Pinho said.

Though the effect was strong, platelet factor 4 won't be a silver bullet that reverses the aging of all tissues and prolongs the lifespan of elderly human patients alone, Pinho said. But it could be a component of other rejuvenation methods to positively affect age-related diseases.

"It's clear evidence that it's possible to reverse, intrinsically, certain age-associated disorders," Pinho said.

Sen Zhang, a postdoctoral fellow in the Pinho lab, is the first author of the study. The work was co-led by Constantinos Chronis from the Department of Biochemistry and Molecular Genetics, who is also a co-corresponding author. Other UIC contributors include Charles Ayemoba, Anna Di Staulo, Kenneth Joves, Chandani Patel, Eva Leung, Maura Bueno, Xiaoping Du and Sang-Ging Ong.