Anemia in older adults

Article written and reviewed by Dr Luca Moretti

Anemia in older adults is one of the most neglected and complex clinical conditions in geriatric medicine. Its prevalence increases with advancing age and it has a profound impact on overall health, quality of life and survival. While in the general adult population anemia often presents as an isolated and often reversible condition, in older adults it frequently acts as a marker of frailty, reflecting multiple pathophysiological processes and systemic vulnerability involving the hematopoietic system, metabolism, immunity, organ function and overall functional reserve.

In community-dwelling populations, the prevalence of anemia averages about 10-12% after age 65 and exceeds 20% especially from age 85; among residents of long-term care facilities it is much higher, with estimates around 48-63%. The operational definition commonly uses hemoglobin cutoffs of <13 g/dL in men and <12 g/dL in women, which are also frequently applied in geriatric studies, while clinical impact depends on comorbidities, rate of onset and physiological reserve. Even mild anemia is associated with mortality, falls, institutionalization and disability, but these associations do not necessarily demonstrate a direct causal relationship.

In geriatric patients, anemia should never be interpreted as a physiological or expected consequence of aging, but as a warning sign of underlying pathological processes, ranging from nutritional deficiency and occult blood loss to chronic inflammation, myelodysplastic syndromes and iatrogenic complications of polypharmacy. Early recognition, etiologic and pathophysiological characterization, and multidisciplinary care are essential to interrupt the vicious cycle linking anemia, functional decline, comorbidity and mortality.

Physiology of hematopoiesis and adaptations in older adults

The hematopoietic system undergoes profound changes with age. The frequency of hematopoietic stem cells may increase, but regenerative capacity and differentiation balance decline, with myeloid bias and alterations of the bone marrow microenvironment; the marrow also undergoes progressive fatty replacement. The erythropoietin response may become inappropriately reduced, particularly in the presence of kidney disease, inflammation or comorbidities.

Another crucial feature is inflammaging, a state of chronic low-grade immune activation characteristic of older age that is associated with persistent secretion of proinflammatory cytokines (IL-1, IL-6, TNF-α), increased hepatic hepcidin and consequent functional sequestration of iron in stores. This reduces iron availability for erythropoiesis, contributes to anemia of chronic disease and is often associated with resistance or a suboptimal response to replacement therapy.

In older adults, the risk of reduced absorption of iron, folate and vitamin B12 increases especially in the presence of associated conditions, including:

• Atrophy of the gastrointestinal mucosa
• Reduced production of gastric acid and intrinsic factor
• Polypharmacy (antacids, proton pump inhibitors, metformin, anticonvulsants)
• Subclinical malabsorptive conditions (celiac disease, pancreatic insufficiency, altered intestinal motility or postoperative changes)

The resulting cumulative vulnerability means that even modest micronutrient loss is sufficient to trigger clinically significant anemia.

Progressive loss of lean mass, depletion of metabolic reserves and the increasing prevalence of dietary deficiencies and protein-energy malnutrition complete the picture of hematopoietic frailty, which is worsened by immobility, reduced oral intake, cognitive impairment and social isolation.

In summary, geriatric hematopoiesis results from a delicate interaction among cellular senescence, altered hormonal responses, reduced micronutrient intake and absorption, chronic low-grade inflammation and multiple diseases.

Classification and Epidemiology

Anemia in older adults is remarkably heterogeneous in both presentation and pathogenesis, reflecting the complexity of biological senescence and the many clinical conditions that accumulate with age. Although traditional morphological classifications, including microcytic, normocytic and macrocytic anemia, remain useful for initial diagnostic stratification, in geriatric practice they are often insufficient to represent the true nature of the problem. The real challenge is not simply identifying the red blood cell phenotype, but recognizing the simultaneous presence of multiple causes, the frequent coexistence of nutritional deficiencies and chronic inflammatory states, and above all the systemic impact of anemia on overall frailty.

In clinical practice, many anemic presentations in older adults are normocytic and normochromic. The etiology may be single, multifactorial or remain unexplained after an adequate evaluation; nutritional deficiencies, inflammation, kidney disease and hematologic disorders may also coexist in the same patient.

From an epidemiological perspective, anemia is common and often underdiagnosed, but estimates vary markedly by age and setting. In community-dwelling populations it affects on average about 10-12% of people older than 65 years and exceeds 20% especially from age 85; among residents of care facilities, estimates are approximately 48-63%. Hospitalization, comorbidity and frailty further increase prevalence.

The growing proportion of unexplained anemia in older adults should also not be overlooked. Even after a complete diagnostic workup, no clear cause is identified in some patients, yet these forms remain associated with a significant increase in the risk of mortality, disability, functional decline and an overall worse prognosis. In these forms, a central role is hypothesized for senescence of the bone marrow microenvironment, altered cytokine regulation, subclinical erythropoietin deficiency and immune dysregulation associated with aging.

Anemia in older adults is clinically relevant because, even when mild, it is associated with reduced physical performance, functional decline, falls, hospitalization and mortality. These associations do not, however, imply that anemia is always the direct cause of the observed outcomes, because comorbidities and frailty make substantial contributions.

Etiology and risk factors

In older adults, anemia may result from a single cause, coexistence of several mechanisms, or remain unexplained after an adequate evaluation. Nutritional deficiencies, chronic diseases, blood loss, kidney or hematologic disorders and iatrogenic factors may occur alone or overlap. With advancing age, the hematopoietic system progressively loses efficiency: stem cell proliferative capacity declines, the bone marrow microenvironment changes and the erythropoietic response to physiological stimuli such as hypoxia becomes less effective. At the same time, older people become more susceptible both to acute insults and to the chronic attrition associated with low-grade inflammation, known as inflammaging, which alters iron regulation and the activity of erythropoietic hormones.

One feature of aging is the increased frequency of occult blood loss, particularly from the gastrointestinal tract, often promoted by conditions such as early malignancies, angiodysplasia, ulcers, diverticulosis and chronic use of NSAIDs or anticoagulants. This is accompanied by a greater risk of reduced intestinal absorption of iron, vitamin B12 and folate related to conditions that become more frequent with age, such as gastric atrophy, hypochlorhydria and reduced intrinsic factor secretion, as well as associated disorders including chronic gastritis, celiac disease, pancreatic insufficiency or previous abdominal surgery.

Equally important, but often underestimated, is the contribution of nutritional deficiencies, which develop insidiously in older adults. Diet may become monotonous and poor in animal protein and essential micronutrients because of financial constraints, social isolation, cognitive decline, dysphagia, depression or reduced independence. Even mild malnutrition increases vulnerability of the erythropoietic system to marginal iron, vitamin B12 or folate deficiencies.

Anemia in older adults is frequently aggravated by chronic diseases such as kidney failure, heart disease, COPD, rheumatoid arthritis, diabetes and occult or early malignancy, as well as by chronic inflammation that limits iron bioavailability and impairs the erythropoietic response. In particular, as chronic kidney disease progresses, the risk of multifactorial anemia increases through a reduced erythropoietin response, abnormalities of iron metabolism and other mechanisms intrinsic to kidney disease.

Finally, polypharmacy is common, although not universal, in older adults and represents an additional risk factor. Numerous drugs, including NSAIDs, proton pump inhibitors, metformin, antiplatelet agents, anticoagulants and chemotherapeutic agents, can directly or indirectly interfere with red blood cell production, nutrient absorption, metabolism or red blood cell survival.

In summary, geriatric anemia reflects an increasingly precarious balance among functional reserve, concomitant diseases and exogenous factors, often compounded by social, cognitive and nutritional frailty that increases diagnostic and therapeutic difficulty. For this reason, anemia in older adults is often the first clinical sign of developing systemic vulnerability and requires comprehensive assessment of every potential causal and aggravating factor.

Pathogenesis and Pathophysiology

The pathophysiology of anemia in older adults reflects the convergence of age-related changes in the hematopoietic system and the multiple clinical factors accompanying senescence. Contrary to the common misconception that anemia is physiological with age, a fall in hemoglobin is never fully explained by aging alone. Even a mild reduction indicates a precarious balance among red blood cell production, nutrient availability, chronic inflammation and associated comorbidities.

At the bone marrow level, hematopoietic stem cells increase in frequency with age but show reduced regenerative capacity, myeloid bias and greater clonal heterogeneity. Reduced erythroid production therefore results mainly from functional decline, an altered microenvironment, inflammation and comorbidities rather than a simple numerical decrease in stem cells.

A fundamental process in older adults is inflammaging, a state of chronic, low-grade but persistent immune activation characterized by continuously increased proinflammatory cytokines such as IL-1, IL-6 and TNF-α and by increased hepatic hepcidin production. Hepcidin, a key regulator of iron metabolism, reduces intestinal absorption and sequesters iron in macrophage stores, limiting its availability for hemoglobin synthesis even when stores appear normal. This mechanism underlies typical anemia of chronic disease in older adults, which is often poorly responsive to oral iron and difficult to correct without controlling the underlying inflammation.

Another critical factor is reduced erythropoietin production, mainly secondary to chronic kidney disease, which may be overlooked even with modest reductions in glomerular filtration, and may be accompanied by altered sensitivity of erythroid progenitors to hormonal stimulation. In addition, the response to erythropoietin is reduced by inflammatory factors, metabolic cofactor deficiencies and cellular senescence.

Nutritional deficiencies involving iron, vitamin B12 and folate often have an insidious pathogenetic role. In older adults, even marginal deficiencies can produce clinically relevant disease because bone marrow functional reserve is reduced. Vitamin B12 deficiency is often related to atrophic gastritis, reduced intrinsic factor or impaired ileal absorption, whereas folate deficiency mainly reflects malnutrition, alcohol misuse or polypharmacy. Iron deficiency frequently results from chronic blood loss, especially from the gastrointestinal tract, which must be investigated; low intake, malabsorption and other causes are also possible.

Finally, anemia secondary to myelodysplastic syndromes (MDS) is not uncommon in geriatric patients. Incidence increases with age, and MDS may initially present as an isolated, subtle abnormality that remains unrecognized for months or years. These disorders, together with idiopathic anemias in which reduced erythroid production has no single explanation, contribute to the group of anemias related to hematopoietic senescence that is increasingly characterized at molecular and immunologic levels.

Some anemias previously classified as unexplained in older adults are now assessed in the context of clonal hematopoiesis. The presence of somatic mutations consistent with CHIP does not by itself demonstrate that the clone causes the anemia. When persistent cytopenia is associated with clonality without meeting diagnostic criteria for a myeloid neoplasm, CCUS may be present, a distinct condition requiring hematologic assessment and follow-up because of its higher risk of progression. Reversible causes and overt MDS must still be excluded before anemia is attributed to senescence or clonality.

Clinical Manifestations

Anemia in older adults rarely presents dramatically. Symptoms tend to be subtle and are often incorrectly attributed to age, comorbidities or general functional decline. The clinical presentation is therefore insidious and requires careful surveillance even when hemoglobin is only modestly reduced.

Initially, symptoms may be limited to weakness, reduced exercise tolerance, easy fatigability, mild dyspnea and palpitations, all of which may be underestimated or masked by chronic conditions such as heart disease, COPD, osteoarthritis or dementia. Unlike younger adults, compensatory tachycardia is often less pronounced because chronotropic reserve is reduced, whereas dyspnea may predominate, particularly during exertion or when pulmonary disease coexists.

A distinctive feature is the association with cognitive and functional impairment. Numerous observational studies show that even mild to moderate anemia is associated with cognitive deterioration, loss of independence, falls and acute delirium during infection or hospitalization, without demonstrating a direct causal relationship for every outcome. Patients may present with reduced alertness, confusion, worsening memory, irritability or emotional instability without classic signs of anemia.

On physical examination, traditional findings such as skin and mucosal pallor, glossitis, cheilosis and brittle nails are often subtle, especially in chronic forms. More advanced deficiency anemia may be accompanied by atrophic glossitis, paresthesias in vitamin B12 deficiency, or subclinical jaundice when hemolysis is present. Most cases, however, are manifested chiefly by worsening of pre-existing conditions, including heart failure, worsening dyspnea, reduced motor performance and increased falls.

Forms associated with chronic diseases or myelodysplastic syndromes are particularly insidious. Slow progression often allows partial adaptation without specific symptoms, but with progressive loss of independence, increasing need for care and, not infrequently, sudden onset of acute events such as syncope, myocardial ischemia, decompensation or delirium after even a minor stressor.

In summary, the clinical picture of anemia in older adults is dominated by loss of functional reserve more than by classic symptoms. Any reduction in hemoglobin should be regarded as a sentinel event, especially when associated with functional deterioration, cognitive decline or increasing cardiovascular, respiratory or infectious complications.

Diagnostic Evaluation

Diagnosis of anemia in older adults requires a systematic and individualized approach that integrates laboratory findings with careful assessment of the clinical history, comorbidities and overall function. Clinical suspicion often arises from nonspecific signs and symptoms or an incidental finding on routine testing, but should always prompt active investigation of the cause because multifactorial disease and reversible conditions are common.

The first step is a complete blood count, interpreted using thresholds commonly applied in geriatric practice as well (Hb <13 g/dL in men and <12 g/dL in women), while recognizing that even borderline values in an older person deserve attention. Red blood cell indices (MCV, MCH, RDW) and the peripheral smear help distinguish microcytic, normocytic and macrocytic patterns, but morphology must always be integrated with comorbidities and clinical history.

Assessment of iron metabolism (serum iron, ferritin, transferrin and transferrin saturation) is essential. Ferritin in particular may be falsely elevated in chronic inflammation and can mask clinically important iron deficiency. The differential diagnosis between iron-deficiency anemia and anemia of chronic disease is based on combined assessment of ferritin, transferrin saturation and inflammatory markers (ESR, CRP). When iron deficiency is documented or suspected, evaluation for a source of blood loss, particularly gastrointestinal blood loss in older adults, should be tailored to age, sex, symptoms and clinical risk, using endoscopy when indicated and not using fecal occult blood testing as an exclusion test.

Vitamin B12 and folate assessment is indicated in all macrocytic forms, in patients with atypical neurologic findings, in malnourished patients and in those taking drugs that interfere with absorption of these micronutrients. In uncertain cases, homocysteine and methylmalonic acid testing may help identify subclinical vitamin B12 deficiency.

Suspected anemia of chronic disease requires careful assessment of comorbidities, including kidney function (blood urea nitrogen, creatinine, glomerular filtration rate), chronic infections, screening for occult malignancy and inflammatory markers. Bone marrow investigations, including aspirate and biopsy, should be reserved for patients with multilineage cytopenias, suspected myelodysplastic syndrome or failure of etiologic treatment.

In geriatric patients, a global functional assessment is also essential. Every diagnosis should be contextualized in relation to cognitive status, independence, fall risk, nutritional status and social support. In this way, anemia is not defined only by laboratory values but becomes part of comprehensive care and an individualized therapeutic strategy.

Treatment and prognosis

Management of anemia in older adults requires a comprehensive, integrated and individualized approach based on identifying the underlying cause and carefully assessing frailty, comorbidities and care priorities. There is no universal therapeutic strategy. Interventions should be tailored to etiology, symptom severity, functional status and the individual patient's goals of care.

Etiologic treatment is the primary objective. Conventional ferrous salts are generally used for iron deficiency; modified-release formulations are not preferred because they release iron more distally, where absorption is lower. Dose and frequency should be adapted to tolerability, with intravenous iron used in cases of intolerance, malabsorption, inadequate response or need for rapid correction.

For vitamin B12 deficiency, the intramuscular route remains the most reliable option when malabsorption is present, while oral treatment can be considered in the absence of severe absorption impairment. Folate deficiency is corrected with oral supplementation, after excluding concomitant vitamin B12 deficiency so that hematologic improvement from folate does not mask untreated B12 deficiency while neurologic injury continues to progress.

In anemia of chronic disease, including inflammaging, kidney failure and chronic inflammatory disorders, treatment requires management of the underlying condition, which is often not fully reversible. Recombinant erythropoietin may be indicated in selected patients with chronic kidney disease and symptomatic anemia after assessment and, where possible, correction of reversible causes and iron status. Erythropoiesis-stimulating therapy in older adults must nevertheless be monitored carefully because of the risk of thromboembolic events and hypertension, particularly in frail patients or those with vascular disease.

Red blood cell transfusion is indicated according to clinical severity, symptoms, rate of hemoglobin decline and comorbidities. Advanced age alone does not justify a higher threshold. In stable adults, a restrictive strategy around 7 g/dL is generally considered, with individualized thresholds, often around 8 g/dL, in selected cardiovascular or perioperative settings. Acute myocardial infarction is an exception: in hospitalized patients with acute myocardial infarction, the 2025 AABB guideline suggests a liberal transfusion strategy when Hb is <10 g/dL, with a conditional recommendation and low certainty of evidence.

Management of bone marrow disorders, including myelodysplastic syndromes and leukemias, requires specialist hematology care. Supportive treatment such as transfusions and growth factors, and disease-modifying therapies such as hypomethylating agents when appropriate, should be evaluated in relation to general condition, life expectancy and patient goals, with particular attention to quality of life and avoidance of unnecessarily aggressive strategies that could worsen frailty.

In geriatric patients, nutritional support and multidisciplinary care are essential components of treatment. Dietary counseling, correction of protein and vitamin deficiencies, treatment of dysphagia and malnutrition, physiotherapy to preserve mobility, adequate social support and review of polypharmacy are indispensable measures for reducing recurrence and the clinical impact of anemia.

Prognosis depends on the cause of anemia, comorbidities and the ability to correct reversible factors. Anemia is associated with mortality, disability, falls and cardiovascular events; etiologic treatment may improve symptoms and function, but a general survival benefit from simply correcting hemoglobin has not been demonstrated.

Complications

The complications of anemia in older adults extend beyond hematologic symptoms and affect physical, cognitive and social health, acting as a powerful amplifier of overall frailty.

From a cardiovascular perspective, anemia is associated with increased risk of heart failure, myocardial ischemia, arrhythmias, worsening coronary symptoms and poorer prognosis in chronic heart disease. Respiratory complications, including progressive dyspnea and worsening COPD or chronic respiratory failure, are also more frequent, especially in already vulnerable patients.

At the functional and cognitive level, anemia is associated with loss of independence, cognitive deterioration, acute confusional states, falls, fragility fractures and slower recovery after acute events. Comorbidities and frailty may contribute substantially to these associations.

Infectious complications are more common in older adults mainly because of immunosenescence, comorbidities, malnutrition, devices and treatments. Anemia may be a marker of frailty but is not a direct immunologic cause of infection, with a greater risk of urinary tract infections, pneumonia and sepsis, often with a more severe course and poorer prognosis in this population.

From a psychosocial perspective, anemia may contribute to social isolation, depression, loss of interest in daily activities and poorer quality of life, reinforcing a vicious cycle of progressive disability.

Transfusion complications, including TACO, immunohematologic reactions and transfusion-transmitted infections, have very different frequencies. TACO in particular is not rare in high-risk patients and is more common in older adults and in people with cardiac or kidney dysfunction. Transfusion should therefore be reserved for true clinical need and accompanied by careful monitoring.

Finally, the risk of underdiagnosis and delayed treatment should not be underestimated. Anemia is too often interpreted as physiological or simply age-related, resulting in missed therapeutic opportunities, deterioration of general condition and increased risk of adverse events.

In summary, prevention, early identification and integrated management of anemia in older adults are essential for reducing the burden of complications, improving prognosis and supporting quality of life in geriatric patients.

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