Unexplained Anemia in the Elderly: Potential Role of Arterial Stiffness

Anemia, as defined by hemoglobin concentration <12.0 and <13.0 g/dl in women and men, respectively, affects more than 150 million elderly people worldwide and even when mild is associated with increased disability, morbidity, and mortality (Ezekowitz et al., 2003; Penninx et al., 2004; De Benoist et al., 2008). The causes of anemia remain unresolved in approximately one-third of anemic older individuals, commonly referred as unexplained anemia in the elderly (UAE; Guralnik et al., 2004). As most types of anemia, UAE is normocytic and its prevalence increases with advancing age (Guralnik et al., 2004). UAE is uniquely characterized by low plasma erythropoietin (EPO) concentration compared to the other forms of anemia (Ferrucci et al., 2007; Artz and Thirman, 2011). Thus, provided that EPO is mainly synthesized in the kidneys and its clearance/degradation is not enhanced, UAEmay be primarily determined by factors affecting renal EPO production and/or hemodilution (Lundby et al., 2014; de Seigneux et al., 2016). These factors are yet to be elucidated. Of note, while hemoglobin concentration is typically employed to diagnose anemia, true (non-hemodilutional) anemia is defined as a decrease in the total volume of red blood cells (RBCV) and/or hemoglobin mass. Herein, we present arguments to support the contention that a fundamental hallmark of vascular aging, arterial stiffness (AS), might be a primary etiological determinant of low EPO concentration and RBCV in UAE via the impairment of mechanisms regulating kidney perfusion, EPO production as well as blood volume. This viewpoint postulates that AS is augmented in UAE patients compared with healthy non-anemic elderly individuals. While direct proof is not available at present, independent lines of evidence demonstrate that UAE is characterized by alterations in biochemical, hematological, and physiological parameters consistently associatedwith AS (Ferrucci et al., 2007; Robinson et al., 2007; Artz et al., 2014;Malahfji et al., 2014), whereof some are described in detail below.