As people grow older, visible changes like gray hair and weaker muscles are only part of the story. Aging also affects the immune system. One major reason is that the stem cells responsible for producing blood and immune cells can accumulate genetic mutations over time, increasing the risk of cancer and other health problems.
Scientists at the University of Illinois Chicago have identified a key biological process behind this shift. Writing in the journal Blood, the researchers report that aging is linked to declining levels of a protein called platelet factor 4. Even more striking, restoring this protein in older blood cells reversed several signs of cellular aging. The findings suggest a potential new target for treating age-related disorders of the blood and immune system.
The Role of Blood Stem Cells in Immune Health
Hematopoietic stem cells, often called blood stem cells, reside in the bone marrow and serve as the foundation of the body's blood and immune systems. These rare cells generate all major types of blood and immune cells needed for oxygen transport and protection against infection.
"Our hematopoietic stem cells are very rare," said UIC's Sandra Pinho, associate professor of pharmacology and regenerative medicine in the College of Medicine. "We call them the Holy Grail of the immune system."
In younger individuals, these stem cells maintain a healthy balance. They produce myeloid cells, which include red blood cells and some immune cells, as well as lymphoid cells, such as T and B cells that play a central role in fighting infections.
Why Aging Stem Cells Lose Balance
As the body ages, blood stem cells begin to favor the production of myeloid cells while generating fewer lymphoid cells. This shift alters immune function and weakens the body's ability to respond to disease.
"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.
This imbalance not only affects immunity but also increases vulnerability to age-related diseases.
Platelet Factor 4 and Stem Cell Control
Through studies in mice and human bone marrow samples, the researchers found that platelet factor 4 plays a central role in regulating blood stem cell behavior. In younger people and animals, the protein acts as a signaling molecule that limits how often stem cells divide. This control is especially important for stem cells that produce myeloid cells.
With age, immune cells produce less platelet factor 4. As a result, stem cells divide more frequently and without proper regulation.
"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 are linked to chronic inflammation, a higher risk of blood cancers, and even cardiovascular disease.
Reversing Signs of Immune Aging in the Lab
The team discovered that restoring platelet factor 4 could counteract these age-related changes. Older mice received daily blood infusions of the protein for more than a month. After treatment, their blood and immune cells showed behavior and characteristics more typical of much younger animals.
Similar effects were observed in laboratory experiments using human stem cells. When platelet factor 4 was added to aged human cells, the researchers saw a clear improvement in stem cell function.
"It rejuvenated the aging of the blood system," Pinho said.
What This Means for Aging and Disease
While the results are promising, platelet factor 4 alone is not expected to reverse aging throughout the entire body or significantly extend human lifespan.
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. However, it could become part of broader strategies aimed at improving age-related conditions.
"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 study's first author. The research was co-led by Constantinos Chronis from the Department of Biochemistry and Molecular Genetics, who also served as a co-corresponding author. Additional contributors from UIC include Charles Ayemoba, Anna Di Staulo, Kenneth Joves, Chandani Patel, Eva Leung, Maura Bueno, Xiaoping Du and Sang-Ging Ong.
