Unexplained Anemia of Aging

Etiology, Health Consequences, and Diagnostic Criteria

Jack Guralnik MD, PhD; William Ershler MD; Andrew Artz MD; Alejandro Lazo-Langner MD; Jeremy Walston MD; Marco Pahor MD; Luigi Ferrucci MD, PhD; William J. Evans PhD


J Am Geriatr Soc. 2022;70(3):891-899. 

In This Article

Therapies for UAA

At the present time, there is no consensus optimal therapy for UAA,[56] in large part because a single targetable deficit has not been characterized. Currently, erythropoietin-stimulating agents (ESA) such as epoetin alfa and darbepoetin alfa are used to treat anemia in patients with chronic kidney disease (CKD), patients receiving dialysis, or in patients with nonmyeloid malignancies where anemia is due to effect of concomitant myelosuppressive chemotherapy.[57] A retrospective analysis[58] of patients with anemia over aged 60 revealed that those with UAA had inappropriately low EPO levels after adjusting for Hb, eGFR, and comorbidities. Gowanlock et al.[59] performed a retrospective analysis of the use of epoetin alfa to treat UAA in 570 patients with anemia over aged 60. They observed a larger increase in Hb in UAA (47%) and CKD (54%) relative to other etiologies (22%) and found that a baseline EPO level < 200 IU/L independently predicted treatment response. Agnihotri et al.[60] conducted a randomized controlled trial to examine the effects of epoetin alfa versus placebo in older (≥65 years; mean age 76.1 ± 7.2 years) women with anemia (Hb ≤ 11.5 g/dl). Patients randomized to epoetin alfa had improved fatigue and QOL relative to the placebo group, and achieved Hb was directly related to improvements in fatigue and QOL. These data imply that patients over the age of 65 years are quite responsive to ESAs.

Idiopathic cytopenia of unknown significance with anemia has been proposed to be synonymous with UAA,[10] and Maggio et al.[61] suggested that UAA is a result of the cumulative effects of age-associated changes in androgen production, low insulin like growth factor 1, and low thyroid hormone levels. At present, however, there is no consensus on the definitive etiology for UAA. Consequently, the diagnosis of UAA is one of exclusion, according to the criteria enumerated in Table 2. The criteria in this table have been somewhat expanded using data published after the paper by Guralnik et al. Moreover, despite strong evidence that even mild anemia is associated with fatigue and reduced quality of life, there is no consensus for treatment options.

Guralnik et al.[18] suggested that patients with UAA may have age-associated deficiencies in the ability to sense hypoxia or erythropoietin (EPO), and consequently require higher rates of erythropoietin production to maintain normal erythrocyte production, a finding supported by data from the Baltimore Longitudinal Study of Aging.[62] Ferrucci et al.[11] separately hypothesized that in many anemic older people, elevated inflammation may prevent EPO from being upregulated sufficiently to meet the need for red cell production.

Several potential treatment options for UAA have been suggested[56] or are in development, including hepcidin antagonists, hypoxia-inducible factor (HIF)-prolyl hydroxylase inhibitors (PHIs), the transforming growth factor beta superfamily ligands, and androgens. The HIF-PHIs are of particular importance. The HIF pathway is a critical component of the cellular response to lower oxygen, and accordingly plays a major role in the regulation of iron metabolism and erythropoiesis. HIF prolyl hydroxylases (PHDs) post-translationally modify HIF, targeting it for degradation by the proteasome; HIF-PHIs prevent this degradation and increase HIF activity under normoxia.[63] Unlike ESAs, which are delivered via injection, this class of drugs is orally delivered small molecules that stimulate production of EPO at physiologic levels. Because a HIF-PHI has been approved for a chronic indication (CKD) in multiple nations, it is reasonable to consider this class of drugs as candidate treatments for UAA.