Mild Pro-Inflammatory State and Anemia in Older Persons.

Aging is characterized by a progressive dysregulation of homeostatic equilibrium. Inflammation is perhaps the most studied aspect of such homeostatic dysregulation, particularly in the context of anemia. Older persons and even “extremely healthy” older individuals are often affected by a mild pro-inflammatory state marked by high levels of pro-inflammatory markers, such as IL-6 and C-reactive protein (CRP). Patients with overt inflammatory diseases tend to develop anemia, usually of mild severity. Four mechanisms by which inflammation may affect anemia have been hypothesized:

1. inhibition of proliferation and differentiation of erythroid precursors by inflammatory cytokines and/or downregulation of the EPO biological response;

2. blunted EPO production;

3. upregulation of hepcidin synthesis and consequent impairment of intestinal absorption and iron recycling; and

4. reduced erythrocyte survival, not fully compensated by increased erythropoiesis.

Studies have shown that the pro-inflammatory state of aging inflammation is associated with EPO levels higher than expected in non-anemic individuals and lower than expected in anemic individuals, suggesting the existence of a pre-anemic state where EPO resistance is compensated by increased EPO levels. Only when this compensatory mechanism fails does anemia become clinically evident. Consistent with this hypothesis, individuals with high EPO and high levels of inflammatory markers are at high risk of developing anemia. The mediating role of hepcidin in the pathogenesis of anemia of inflammation is suggested by an extensive literature. By interacting with the unique iron transporter, ferroportin, hepcidin controls iron intestinal absorption and mobilization from hepatocytes and macrophages, thereby causing low serum iron and ineffective erythropoiesis. Patients affected by disease characterized by overt inflammation, such as rheumatoid arthritis, abscess, and sepsis, show increased hepcidin urinary excretion. There is some evidence that the mild-pro-inflammatory state of aging does not cause hepcidin upregulation, although it is associated with low serum iron, lower transferrin saturation, and higher ferritin concentration. Thus, the iron lowering effect of moderate inflammation may be mediated by some still-unknown mechanism other than hepcidin. Studies are needed to test the hypothesis that the mild inflammation affects erythrocyte lifespan.