• When blood-forming hematopoietic stem cells that reside in the bone marrow age, the production of blood cells is altered, and the body’s ability to regenerate lost cells is impaired.
• A recent study in mice shows that aging is linked to the inflammation of cells in the bone marrow.
• The researchers saw that treatment with Anakinra—an interleukin (IL-1) receptor blocker approved for the treatment of rheumatoid arthritis—could help mediate this impaired functioning.
• This suggests that treatments targeting IL-1 signaling may have the potential to ameliorate the effects of aging on blood production.

The aging of hematopoietic stem cells (HSCs) is characterized by the impaired ability of these cells to regenerate and produce blood cells.

A recent study conducted in mice shows that blocking the receptor for the proinflammatory protein IL-1 using the FDA-approved rheumatoid arthritis drug Anakinra may attenuate the deficits in the functioning of hematopoietic stem cells due to aging.

These findings, published in Nature Cell Biology, suggest that inhibiting IL-1 function could potentially improve deficits in blood production in older adults.

Aging of blood-producing cells

The bone marrow is the soft, spongy tissue found at the center of most bones in the body.

The bone marrow is located in a central marrow cavity and is surrounded by a thin membrane called the endosteum. The bone marrow is the main site for hematopoiesis, the process of new blood cells forming via the hematopoietic stem cells (HSC) dividing and differentiating.

Besides producing daughter HSCs after cell division, HSCs also produce different progenitor cell types that, in turn, divide to produce specific types of mature blood cells. These mature blood cells include red blood cells (erythrocytes), white blood cells (leukocytes), and cells belonging to the myeloid lineage.

Myeloid cells, in particular, include macrophages, platelets, monocytes, and granulocytes, several of which play an important role in producing an immune response.

The bone marrow niche

Besides housing hematopoietic stem cells and their progeny, the endosteum and the central marrow also contain distinct cell populations that express molecules or secrete proteins, such as cytokines that regulate the formation, development, and function of HSCs and progenitor cells. All these cells, along with blood vessels and the extracellular matrix, form the bone marrow niche.

The bone marrow niche includes cells belonging to the stroma, which includes mesenchymal stromal cells, adipocytes (fat cells), nerve cells, connective tissue cells, and cells involved in bone formation and remodeling. Mesenchymal stromal cells can divide and differentiate into a number of cell types, including bone, cartilage, and adipocytes.

The bone marrow is rich in blood vessels, consisting of arteries, arterioles, capillaries, and sinusoids. Arteries transport oxygenated blood from the heart to smaller branches called arterioles that subsequently supply sinusoids.

Sinusoids are specialized blood vessels and are highly permeable. The endothelial cells that form the lining of these blood vessels are also a major part of the bone marrow niche.

The study found that bone marrow niche cells that support the functioning of HSCs played a key role in blood aging.

Aging and hematopoiesis

Aging is associated with a decline in the function of the hematopoietic stem cells. These changes in the hematopoietic system include a decline in the ability of HSC to produce new HSC and progenitor cells, especially those that produce white blood cells.

These age-related changes can be manifested as anemia, a subdued immune response, increased susceptibility to diseases, and even cancer.

Although aging also influences the bone marrow niche, how these changes in the bone marrow niche influence hematopoietic aging is less studied.

In the present study, the researchers performed several analysis in the hindlimb, forelimb, and pelvic bones from young and old mice to examine the impact of aging on the interaction between the bone marrow niche and hematopoietic cells.

Aging’s impact on bone marrow niche

The present study found that aged mice showed a decrease in the population of mesenchymal stromal cells and osteoprogenitor cells that are involved in bone formation in the endosteum. In contrast, there was an increase in the number of mesenchymal stromal cells in the central marrow of aged mice.

However, a significant fraction of these mesenchymal stromal cells in the central marrow cavity expressed inflammatory markers. In addition, there was a loss of endothelial cells lining the sinusoids and an alteration of the sinusoidal vessels

Further analysis of the gene expression profile of aged mice revealed an increase in the expression of inflammatory genes across the bone marrow niche cells.

The increased inflammation in the bone marrow niche of aged mice was mediated by elevated expression and secretion of certain inflammatory cytokines, including IL-1β, by endosteal stromal cells.

Moreover, IL-1β secreted by endosteal stromal cells was sufficient to modulate the activity of the HSC.

Finding the source of inflammation

“[We identified] bone-forming ‘osteoprogenitor’ cells in the bone marrow niche as an unexpected source of inflammatory signals in older animals, in particular IL-1. Strikingly, by using an FDA-approved drug for rheumatoid arthritis called Anakinra that specifically blocks the effects of IL-1, we were able to restore youthful blood production to old mice,” the study’s author Dr. Emanuelle Passegué, director of the Columbia Stem Cell Initiative, said.

“Consistently, aged animals that genetically lacked the cellular receptor for IL-1 had a healthier niche and blood system than their unmodified counterparts. This indicates that inhibiting IL-1 signaling is a useful strategy for maintaining efficient blood production in the elderly,” continued Dr. Passegué.

“More generally, it also provides a roadmap for the identification and harnessing of specific biomolecules to improve tissue function during aging,” he added.

How inflammation affects stem cells

The increase in niche inflammation in old mice also had an adverse impact on hematopoietic stem cells and their progeny.

Scientists observed that an increase in inflammation in niche cells was linked to an increase in how HSC and progenitor cells differentiated into myeloid cells, such as macrophages and granulocytes, and platelet cells.

In contrast, researchers saw a decline in the differentiation of progenitor cells into lymphocytes—a type of white blood cell— and red blood cells in the bone marrow of old mice.

Aged mice also showed an impaired ability to regenerate hematopoietic stem cells and blood cells after being exposed to 5-fluorouracil, a chemical that causes dividing bone marrow cells to deplete.

These results suggest that age-related inflammation in the bone marrow niche also produces changes in the hematopoietic compartment.

2 weeks of treatment with Anakinra

Previous studies have shown that treatment with the cytokine IL-1β can recapitulate the effects of aging on hematopoietic cells.

Here, the researchers found that IL-1β treatment also mimicked the effects of aging on the bone marrow niche, including alterations in the sinusoidal vessels and a decline in the stromal cell population in the endosteum.

Moreover, treatment with the IL-receptor blocker Anakinra for two weeks helped attenuate the effects of 5-fluorouracil on hematopoietic cell regeneration in old mice.

Genetically engineered mice lacking the receptor for IL-1 signaling also showed a limited impact of aging on the bone marrow niche composition, including lower levels of inflammatory mesenchymal stromal cells in the central marrow and limited loss of endosteal stromal cells after treatment with Anakinra.

Lifelong genetic inhibition of IL-1 signaling also resulted in fewer signs of blood aging but did not completely eliminate the effects of aging. These mice lacking the IL-1 receptor showed lower myeloid cell production, anemia, and reduced loss of lymphocytes.

Interleukin-1: The culprit behind aging?

In sum, these results suggest that IL-1 released by stromal cells in the bone marrow endosteum could play a role in causing inflammation in the bone marrow niche and hematopoietic cells, eventually leading to the aging of the blood-producing cells.

Notably, these results, pending research in humans, suggest that inhibiting IL-1 signaling could potentially be used for the regeneration of HSCs and their progenitors in older individuals or after chemotherapy or other treatments that lead to impaired hematopoiesis.

However, further research is needed before therapeutics targeting IL-1 function can be used to improve hematopoietic regeneration.

“Our study was performed in mice, which share many features of blood aging with humans. Further validation of our findings with human cells is warranted, as well as epidemiology looking at healthier blood production in Anakinra-treated elderly patients to justify clinical trials,” Dr. Passegué said.

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