To explore the first two hypotheses, Ferrucci et al. studied how inflammation affects the relationship between hemoglobin (Hb) and erythropoietin 11. Unexpectedly, higher inflammation was associated with an EPO level higher than expected in participants free of anemia, and lower than expected in anemic participants (Figure 2). These findings suggest that inflammation hampers the response to EPO (because of either EPO signal jamming or intrinsic bone marrow dysfunction). In the early stage of anemia development, this defect is fully compensated by increased EPO production. However, subsequently, when the ability to over-produce EPO is exhausted, anemia becomes clinically manifest. Ongoing studies are testing the hypothesis that subjects with high EPO and high levels of inflammatory markers (especially IL-6 and CRP) have high risk of developing anemia. Accordingly, there is preliminary evidence that older subjects with high levels of inflammatory markers and high EPO are at high risk of developing anemia. If confirmed, these findings will have important clinical implications because they indicate that a condition of high inflammation and “inappropriately” high EPO levels mark a condition of “preclinical anemia.” If these subjects at high risk of developing overt anemia after hemopoietic stress could be identified, preventive or supportive strategies could be implemented at an early stage.

Inflammation is perhaps the most studied element of the homeostatic network dysregulation, particularly in the context of anemia. Aging is characterized by a progressive mild pro-inflammatory state which is revealed by rising levels of pro-inflammatory markers (Figure 1) 27. Although this phenomenon can be partially explained by increasing prevalence of chronic disease and other risk factors with age, even when the effect of these factors is taken into account and even when “extremely healthy” individuals are selected, older individuals still have higher levels of Interleukin-6 (IL-6) and other pro-inflammatory cytokines and acute phase reactive proteins. Evidence is accumulating that such a pro-inflammatory state is a strong independent risk factor for a number of negative health-related outcomes, including cardiovascular disease, disability, cognitive impairment and short-term mortality 28–32. The mechanisms underlying this association are still under investigation.