Targeting protein restores aging blood cells, UF researchers find

GAINESVILLE, Fla. — As humans age, we develop chronic inflammation in our blood and tissues that gradually decreases the function of blood stem cells in our bone marrow. These defects harm blood cell production and the immune system, often leading to a slew of complications and weakening responses to chemotherapy.

Now, UF Health Cancer Center researchers have discovered a way to prevent this inflammation, called “inflammaging,” by systemically targeting a protein. The findings in mice, published Jan. 3 in Science Immunology, could pave the way for therapies aimed at preserving an aging blood system, with implications for cancer treatments and aging-related diseases, including anemias, infections, and blood cancers.

“We set out to determine if we could fully preserve and rejuvenate blood stem cell function during the course of aging, a goal that had remained largely elusive so far,” said Jason Butler, Ph.D., a professor and vice chief of research in the UF Division of Hematology and Oncology and a member of the UF Health Cancer Center, who led the new study.

“We found that by suppressing chronic inflammation in aged mice,” he said, “we could preserve blood stem cell function and other metrics of aging, like bone density, vascular integrity, and changes in gene expression profiles.”

Everyone experiences some inflammation as they age, but factors like obesity, smoking, past surgeries, or even lack of sleep can worsen it. Interventions such as calorie restriction and exercise can reduce this inflammation in other types of cells, but they don’t have much effect on aging blood stem cells, Butler said. These earlier findings suggested that older adults’ stem cell decline was inevitable.

Butler’s team previously found that interfering with the interaction of blood stem cells with the bone marrow microenvironment caused mice to age faster. These studies led them to identify a protein, thrombospondin-1, that plays a critical role in controlling chronic inflammation and speeds up aging.

In the new study, the researchers treated young blood stem cells with thrombospondin-1. The results were startling: The cells functioned as if they were old. When the researchers blocked the function of thrombospondin-1, the observations were reversed.

“The old stem cells essentially behaved as if they were young, rejuvenating the blood system,” Butler said. “In addition to improving the health span of the blood system, deletion of thrombospondin-1 also preserved bone mineralization and vascular health in aged mice and significantly increased the lifespan of the mice.”

Pradeep Ramalingam, M.D., Ph.D., a research assistant professor in the Division of Hematology and Oncology and the study’s first author, is leading efforts to test whether thrombospondin-1 plays a role in regulating human blood stem cells, with the hope of testing in clinical trials.

“A lot of times, patients receiving chemotherapy experience serious side effects because their blood system can’t handle the toxicity of the treatment,” Ramalingam said. “Protecting the blood and vascular systems by blocking thrombospondin-1 could potentially allow patients to recover faster.” This would be particularly important for older patients with cancers like acute myeloid leukemia, Butler said. Such patients often cannot receive as much chemotherapy as pediatric patients because their blood system can’t withstand it.

To advance the research, the team also developed a genetic signature for measuring inflammaging in blood stem cells, which can be used by researchers studying stem cell aging.

The new study was funded in part through grants from the National Institute on Aging and the National Heart, Lung, and Blood Institute, both part of the National Institutes of Health, and the American Federation on Aging Research.