Reducing Iron May Reverse Stem Cell Aging

Researchers at the Albert Einstein College of Medicine and the National Cancer Institute-designated Montefiore Einstein Comprehensive Cancer Center (MECCC) have discovered a way to prevent or even reverse the function of hematopoietic (blood-forming) stem cells (HSCs) as they age.

This is achieved by reducing iron levels in these adult stem cells, which helps to produce new red and white blood cells and other vital blood components and contributes to chronic inflammation, ultimately accelerating the onset of blood cancers and degenerative diseases. The study findings were published in the journal Cell Stem Cell.

We’ve shown that this decline in HSC function is not inevitable and appears to be reversible. By lowering iron levels inside the cell with a clinically available drug, we were able to restore a youthful pool of HSCs in older mice. This simple treatment strategy holds promise for slowing aging-related diseases as well as chronic inflammatory diseases and blood cancers.”

Britta Will, Ph.D., Associate Professor, Study Senior and Co-Corresponding Author, Department of Medical Oncology, Department of Cell Biology, Albert Einstein College of Medicine

An Unexpected Role for Iron in Blood Stem Cells

This study began in 2018 when Dr. Will and associates noticed that eltrombopag, a medication used to increase platelet counts, also stimulates HSC activity. At that point, the researchers found that eltrombopag chelates iron from HSCs, which is why this improvement happens. Their recent research revealed that the fate and function of HSCs are determined by the amount of iron within the cells.

After examining HSCs, the researchers discovered that too much intracellular iron causes inflammation in the cells and drives them into dormancy, a state characterized by drastically reduced cell activity that is comparable to animal hibernation.

Dormancy reduces HSCs' capacity to proliferate and generate adequate high-grade red blood cells. On the other hand, HSCs with low iron levels proliferate quickly and function well when additional blood components are required.

So basically, iron restriction governs and protects the regenerative capacity of stem cells - their ability to divide and to differentiate into blood cells.”

Yun-Ruei Kao, Ph.D., Research Assistant Professor and Study Co-Corresponding Author, Department of Oncology and of Medicine, Albert Einstein College of Medicine

How does iron restriction preserve the health of HSCs? In research involving young mice, the researchers discovered that low iron causes HSCs to undergo a molecular reaction that momentarily boosts fatty acid metabolism and strengthens HSC genetic programs after the cells have multiplied in young animals.

In contrast, it was observed that aged mice's HSC had higher iron levels, which prevented this recently identified fatty-acid metabolism pathway from being activated.

Next, the researchers investigated whether or not older and aging mice's blood-cell production would be enhanced by removing iron from HSCs. The team injected the iron chelator deferoxamine daily into aged mice for a period of 14 days to lower the iron levels in HSCs. After their HSCs were transplanted into other mice, aged HSCs exposed to iron chelation produced a significant increase in blood cells compared to controls.

Extended iron chelation had an even more noticeable effect: the HSCs of 6-month-old (middle-aged) mice showed up to a 10-fold increase in regenerative capacity compared with controls when the animals were given an iron chelator for 13 additional months (well into old age).

To our knowledge, this is the first time that a non-invasive strategy has successfully rejuvenated stem cells. But like all experimental strategies, it needs to be assessed in a clinical setting to make sure it’s safe and effective.”

Britta Will, Ph.D., Associate Professor, Study Senior and Co-Corresponding Author, Department of Medical Oncology, Department of Cell Biology, Albert Einstein College of Medicine

Aging and Iron Intake

Physicians frequently recommend seniors take iron supplements or eat more foods high in iron because aging is frequently linked to systemic iron deficiency. The risk of iron deficiency anemia, the root cause of many health problems, is reduced by taking this additional iron.

According to Dr. Will, those suggestions are still valid. According to her, as humans age, the bodies' ability to metabolize iron can deteriorate, resulting in iron overload in certain organs like the bone marrow, which is home to a large number of HSCs, and iron deficiency in others.

Dr. Will added, “Our study’s key finding - that chelators, by neutralizing iron loading inside HSCs, may enable HSCs to remain healthy into old age - is potentially important. To our knowledge, this is the first time that a non-invasive strategy has successfully rejuvenated stem cells. But like all experimental strategies, it needs to be assessed in a clinical setting to make sure it’s safe and effective.”

Dr. Will is currently investigating the relationship between HSCs and iron from a number of perspectives, including how to safely restrict HSCs' access to iron as they age, whether limiting HSCs' access to iron can stop them from transforming into cancerous HSCs as they age, and how much other adult stem cells - like those found in the gut - need iron restriction in order to regenerate tissues and organs consistently.