As we age, our hematopoietic stem cells (HSCs)—the cells responsible for producing new blood cells—become less efficient, leading to chronic inflammation and increasing the risk of blood cancers and degenerative diseases. Researchers at Albert Einstein College of Medicine and the Montefiore Einstein Comprehensive Cancer Center (MECCC) have discovered that this decline in HSC function can be prevented or even reversed by reducing iron levels in these cells. The findings were published on March 7 in the journal Cell Stem Cell.
“We’ve demonstrated that the decline in HSC function is not inevitable and can be reversed,” said study senior author Britta Will, Ph.D., associate professor at Einstein and co-leader of the stem cell and cancer biology program at MECCC. “By lowering iron levels inside the cells with a clinically available drug, we restored a youthful pool of HSCs in older mice. This simple treatment strategy shows promise for slowing aging-related diseases, chronic inflammatory diseases, and blood cancers.”
The Role of Iron in Blood Stem Cells
The research began in 2018 when Dr. Will and colleagues found that eltrombopag, a drug used to increase platelet levels, also stimulates HSC activity by removing iron from these cells. Their new study reveals that the amount of iron within HSCs determines their fate and function. Excess iron triggers inflammation within HSCs, pushing them into dormancy, a state where their functions are significantly slowed. This limits their ability to replicate and produce high-quality blood cells. Conversely, HSCs with restricted iron levels can multiply and respond effectively when more blood components are needed.
“Essentially, iron restriction protects the regenerative capacity of stem cells—their ability to divide and differentiate into blood cells,” said co-author Yun-Ruei Kao, Ph.D., research assistant professor at Einstein.
### Mechanism of Iron Limitation
In studies with young mice, the researchers found that low iron levels activate a molecular response in HSCs that temporarily boosts fatty acid metabolism, enhancing genetic programs in HSCs. In aged mice, increased iron levels inhibited this metabolism pathway. To test whether reducing iron levels in HSCs would improve blood-cell production, the team injected old mice with the iron chelator deferoxamine for 14 days. The treated aged HSCs produced significantly more blood cells compared to controls. Long-term iron chelation in middle-aged mice also resulted in a significant increase in regenerative capacity.
Ageing and Iron Intake
Though aging is often associated with systemic iron deficiency, leading to recommendations for iron supplements, this study indicates that iron metabolism can deteriorate, causing iron overload in some organs, including the bone marrow. Dr. Will emphasized the importance of their finding that chelators can rejuvenate HSCs by neutralizing iron loading, but she also noted the need for clinical assessment to ensure safety and effectiveness.
Dr. Will continues to explore how to safely limit iron in HSCs during aging, prevent their transformation into cancerous cells, and determine if other adult stem cells depend on iron restriction for tissue and organ regeneration.
