Tumor Necrosis Factor-Alpha and Involuntary Weight Loss in Elderly, Community-Dwelling Adults

J. Mark Ruscin, Pharm.D.; Robert L. Page II, Pharm.D.; Bryan F. Yeager, Pharm.D.; Jeffrey I. Wallace, M.D.

Disclosures

Pharmacotherapy. 2005;25(3):313-319. 

In This Article

Abstract and Introduction

Study Objective: To evaluate the association between involuntary weight loss and serum concentrations of tumor necrosis factor (TNF)-α in elderly, community-dwelling adults. Design: Cross-sectional, single–time point investigation.
Setting: Two primary care ambulatory clinics.
Subjects: Ambulatory adults aged 70 years or older with involuntary weight loss of 2.27 kg (5 lbs) or more, or with stable weight (B1 0.91 kg [2 lbs]) for the 3 months before enrollment.
Measurements and Main Results: Ten subjects with weight loss (mean B1 SD -4.9 B1 2.6 kg) and 25 subjects with stable weight (+ 0.06 B1 0.55 kg) were enrolled. The latter group was recruited to serve as a comparison group to the weight-loss group. Subjects donated a venous blood sample and were administered the Mini Nutritional Assessment at a single clinic visit. Serum concentrations of TNF-α were measured by using enzyme-linked immunosorbent assay. The TNF-α concentrations were significantly higher in subjects with weight loss (mean B1 SD 19.3 B1 24.9 pg/ml) than in subjects with stable weight (mean B1 SD 1.1 B1 2.0 pg/ml, p < 0.01). No relationship was found between the TNF-α concentration and the degree of weight loss expressed as a percentage of total body weight.
Conclusion: Older adults with involuntary weight loss had increased circulating concentrations of TNF-α. Whether TNF-α plays a causal role in involuntary weight loss among older adults is unclear; however, this finding is consistent with those in other disease states associated with cachexia. Further research is necessary to clarify this relationship and to determine if pharmacotherapeutic interventions targeted at TNF-α can prevent or reverse involuntary weight loss and its associated morbidity and mortality.

Involuntary weight loss is a common phenom-enon in older adults, with an annual incidence of approximately 13%.[1] The clinical consequences of involuntary weight loss include functional decline, infections, decubitus ulcers, exacerbation of cognitive and mood disorders, and increased utilization of acute care and nursing home care.[2–9] Weight loss is also predictive of mortality in both nursing home residents and community-dwelling elderly individuals, regardless of the underlying cause.[1–3] In a study of older veterans, involuntary weight loss greater than 4% of their body weight was associated with increased risk of mortality, with a 2-year mortality rate of 28%.[1] Although weight loss in older persons has many etiologies, including depression, malignancy, ill-fitting dentures, and failure to thrive, diagnostic workup often fails to reveal a specific reversible cause.

Although involuntary weight loss is common in older adults, the pathogenesis is poorly under-stood. Evidence suggests that the immune system may play an important role in the development of involuntary weight loss and cachexia.[10,11] Inflam-matory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, have been implicated in cachexia and weight loss.[10–13] Historically recognized as cachectin, TNF-α is generally considered one of the more pertinent cytokines and thought to be the primary mediator of muscle wasting in cachexia; it is also believed to act synergistically with IL-1β to promote cachexia. Serum concentrations of TNF-α are increased in several human disease states associated with cachexia and weight loss, including malignancy, acquired immunodeficiency syndrome, heart failure, rheumatoid arthritis, and chronic obstructive pulmonary disease.[13–18] Cytokines may act both centrally by inhibiting feeding and peripherally by decreasing gastric motility, gastric emptying, intestinal motility, and modifying gastric acid secretion.[11,12] In addition, TNF-α reduces gastric emptying and peristalsis, induces lipolysis and inhibits lipid synthesis, and increases proteolysis in peripheral muscle tissues.11, 12, 18 Both TNF-α and IL-1β are thought to alter the balance between protein degradation and protein synthesis, shifting the balance toward protein degradation. Reduced peripheral insulin action, which may occur in the presence of increased TNF-α, may also create an environment favorable to cytokine-induced muscle degradation.[18,19] Cachexia syndromes typically do not respond to hypercaloric feeding; therefore, exploring the underlying mechanisms is vital to understanding and developing treatments for cachexia and involuntary weight loss.

The biologic mechanisms of cachexia and weight loss in older adults have received compar-atively little attention in the published literature.[13] One study did not find a relationship between weight loss and TNF-α or IL-1α concentrations in ambulatory elderly persons and nursing home residents.[20] However, the same researchers later found that detectable TNF-α was a predictor of mortality in older nursing home patients.[21]

Pharmacotherapeutic interventions to suppress TNF-α production and/or activity have met with mixed results. Most studies have involved patients with cancer, human immunodeficiency virus infection, or pulmonary or cardiac conditions.[22–25] One study showed that reduced concentrations of cytokine receptors, including TNF-α receptors, were correlated with weight gain in older patients treated with megestrol.[26] However, progestative agents such as megestrol have demonstrated the potential for adverse effects on the metabolic, cardiovascular, and central nervous systems.[11,27]

An improved understanding of the mechanisms that regulate involuntary weight loss and cachexia in older adults is needed to identify and develop safe and effective therapeutic alternatives. We sought to determine if elderly community-dwelling adults with involuntary weight loss have circulating TNF-α concentrations higher than those of older adults with stable weight.

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