Inflammation Accelerates Hematopoietic Aging

Researchers in Germany have discovered that mice that experience inflammation in early to mid-life show a decline in functional blood stem cells and develop clinically relevant features of aging. The findings suggest that infection and inflammation may act as a prominent driver of age-associated functional decline in tissues.

Blood stem cells in the bone marrow provide a lifelong replenishment of the different cell types making up the blood system. They are also of capable of making new stem cells. But in old age, diseases of the hematopoietic system such as anemia or certain forms of blood cancer often occur. Such diseases are thought to be caused by an age-associated decline in stem cell self-renewal, although mouse models housed under highly controlled, pathogen-free conditions, rarely spontaneously develop such age-related conditions.

Mick Milsom of the German Cancer Research Center and the Stem Cell Institute HI-STEM said the study set out to answer whether inflammation and infections in early life can permanently damage blood stem cells and thus promote aging of the blood system. "We have therefore carried out time-consuming experiments to determine for how we observe an inhibitory effect on stem cell function following infection and inflammation, and came to the surprising conclusion that we never see any evidence of stem cell recovery, suggesting that this process is long-lasting or perhaps even irreversible," he says.

The work, published in the journal Cell Stem Cell, gave mice injections of pro-inflammatory substances or bacteria several times with four-week intervals between. The lack of stem cell recovery between each round meant that these treatments resulted in an additive inhibitory effect, supporting a model that explains age-associated tissue dysfunction and disease: where separate instances of infection or inflammation can have a cumulative inhibitory effect on stem cell function, even if separated by months or years.

The researchers subsequently identified the cause of the dysfunctional hematopoiesis; blood stem cells failed to self-renew as they were forced to divide in response to the inflammatory stimuli. The long-term consequence of a lack of self-renewal is that the hematopoietic system becomes exhausted.

"This observation in mice contradicts common doctrine: we had previously believed that, after inflammatory challenge, blood stem cells revert into a so-called dormant state that preserves their capacity for self-renewal," says Milsom.

Notably, the inflammation in young mice led to persistent changes in the hematopoietic system resembling age-related changes often found in elderly people. These include anemia and decreased number of cells in the bone marrow.

"Inflammation and infection at a young age appear to accelerate the aging of the hematopoietic system," Milsom said. "Our next challenge is to explore whether prophylactic anti-inflammatory treatment could delay the development of age-related diseases of the blood system, while still preserving the immune response against pathogens."