“Anemia — a common but never normal concomitant of aging”

~R. Lewis 1976 (1)

The word anemia was originally derived from the ancient Greek (An = not; haema = blood). In 1958, the World Health Organization (WHO) defined anemia as a hemoglobin concentration less than 13g/dl in men and less than 12g/dl in women. These values have been utilized for the last 50 years despite the fact that these values were not necessarily evidence-based and that numerous studies, especially in males, have suggested that the values should be higher. In 2006 Beutler and Waalen (2) utilized a large number of subjects in the WHANES-III and the Scripps-Kaiser database to more accurately determine normal values. They excluded subjects with diabetes mellitus, renal failure, elevated inflammatory markers, and those with low serum ferritin and transferrin because these frequently impact the hemoglobin level. They concluded that 13.7 g/dl in white males and 12.9 g/dl in black males were the appropriate normal hemoglobin levels for those under 60 years of age and 13.2 g/dl (white), and 12.7 g/ dl (blacks) were normal for those greater than 60 years of age. In females, hemoglobin levels of 12.2 g/dl in whites and 11.5g/dl in blacks were found to be normal levels for women of all ages. Race impacts hemoglobin levels, with black people having lower levels, likely due to the high frequency of alpha-thalassemia genes (and potentially yet un-discovered genes) in this population.

A large meta-analysis found that using the original WHO criteria, 17% of older persons were anemic (3). However, when a hemoglobin level of <11 g/dl was used, that percentage increased to 76%. In this study, anemia was found to be more common in males than in females and more common in black people than in white people. Anemia increases with age with prevalence being as high as 2.3% to 31% in the oldest of old. There is also a large geographical variation. In one study, the prevalence of anemia in Minnesota was found to be 7% in older women and 9% in older men (4), whereas, in the English Longitudinal Study of Aging, which included study participants living in England, only 5.2% were found to be anemic (5). In nursing homes, anemia is quite common; the prevalence ranging from 47% to 60% (6). Furthermore, studies have demonstrated that persons with anemia are more likely to be frail (7–9), fatigued (10), have impaired grip strength (11), have decreased functional status (12), more likely to fall (13), have fractures (14), be cognitively impaired (15) and have overall increased mortality (16) than their non-anemic counterparts.

The causes of anemia can be classified as those with an elevated reticulocyte index (which is the reticulocyte count corrected for hemoglobin) and those with a low reticulocyte index (Table 1). Those with an elevated reticulocyte count are either due to blood loss or hemolysis. Nutrient deficiency—i.e., vitamin B12, folate, riboflavin, and copper deficiency or protein energy malnutrition, or decreased production of red blood cells (seen in anemia of chronic disease/inflammation, anemia of chronic kidney disease—defined by the lack of erythropoetin plus inflammation, and myelodysplastic disorders) are the common causes of anemia with a low reticulocyte index. In older persons about 20% of anemia has no clear explanation and has been termed the anemia of old age (17).

Table 1 Causes of Anemia in Old Age
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Aging and Iron Status

Serum levels of iron and transferrin typically decline with aging (18). Conversely, serum ferritin levels increase until around 60 years of age after which they plateau (19). Additionally, serum ferritin levels are increased with inflammation, which requires a compensatory increase in serum ferritin “normal” levels from 20 μg/L to 40μg/L to improve the sensitivity in diagnosing iron deficiency anemia. For this reason, a C-reactive protein (CRP) should be measured in conjunction with ferritin levels and helps one distinguish between iron deficiency anemia and anemia of chronic disease/inflammation.

The soluble transferrin receptor (STfR) plays an important role in delivering iron to erythroid precursors. Because its levels rise when there is a shortage of intracellular iron, it is less sensitive to the effects of chronic inflammation. The STfR/log ferritin index is considered a good measure of iron deficiency because it represents a true estimate of total body iron stores (20, 21). Fibroblast Growth Factor, which increases with low iron measures, has been suggested as an alternative measurement (22).

Hepcidin, which is released from the liver in response to the inflammatory cytokine, interleukin-6, inhibits the function of the iron transporter, ferroportin (Figure 1). This decreases iron absorption from the gut and prevents release of iron from macrophages into the bloodstream (23). The measurement of SSTfR/Hepcidin index may be a useful measure to predict iron deficiency (24). The role of hepcidin in the pathogenesis of the anemia of chronic disease has led to the development of a number of hepcidin antagonists (antibodies, antisense oligonucleotides and RNA interference) as potential therapeutic agents (25) in anemia of chronic disease/inflammation.

Figure 1
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The role of hepcidin in the anemia of chronic disease

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Anemia of Old Age

One possible etiologic factor for the anemia of old age is the reduction in bone marrow erythroid progenitors (26), which downstream, decreases the amount of red blood cells released into the circulation. The reduction in bone marrow cellularity begins at 30 years of age and is of the order of 30% to 50% in persons over 60 years of age. These reductions in red cell progenitors are due to epigenetic changes, oxidative damage, or reduction in telomere length. Clonal hematopoieses of indeterminate potential are relatively common in older persons, frequently presenting with mild leukopenia and anemia and may be an unrecognized cause of anemia of old age.

The cytokine-related aging process or “inflamm-aging” also contribute to the anemia of old age (27). Older persons have an increase in adiposity which increases chronic inflammation and leads to increased hepcidin production(28) In addition, in older persons there is often a decrease in erythropoietin production and also a decline in receptor sensitivity to erythropoietin (29). Eryptosis (apoptosis of red blood cells) can be stimulated by inflammation (30). With aging, phosphatidylserine moves to the red cell surface, making the red cells more susceptible to being ingested by macrophages. Protein energy malnutrition, which is common in older persons, also leads to anemia (31, 32).

Testosterone levels decline in males with aging, resulting in a lowering of the hemoglobin and hematocrit (33). Testosterone administration in hypogonadal males reverses this process and leads to an increase in erythropoietin levels and a decrease in hepcidin. This decrease in hepcidin results in an increase in ferroportin expression, leading to increased iron absorption and release into the circulation (34, 35).

The causes of anemia of old age are summarized in Figure 2 and the diagnostic characteristics in Table 2.

Figure 2
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Etiology of the Anemia of Old Age

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Table 2 Comparison of Anemia of Old Age with Iron Deficiency Anemia and Anemia of Chronic Disease
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Conclusion

Anemia is a common condition in older persons. There are a variety of treatable causes and when anemia is identified physicians should follow a simple diagnostic algorithm to make the appropriate diagnosis (Figure 3).

Figure 3
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Algorithm for Diagnosis of Anemia in Older Persons

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Disclosures: The authors declare there are no conflicts.