Aging is associated with remodeling of the immune system, contributing to increased incidence of infections, autoimmune diseases, and cancer among the elderly. Alterations in several signal transduction pathways have been reported to play an important role in immunosenescence. We show that peripheral blood leukocytes obtained from old donors (> or =65 years) have a significantly reduced expression of receptor for activated C kinase 1 (RACK-1), a protein required for protein kinase C (PKC)-beta signaling, as compared with young donors (< or =40 years), both in males and females. The decline in RACK-1 immunoboth in reactivity was age-related (Spearman correlation, r=-0.278, P=0.012). All leukocyte subpopulations, namely lympho-monocytes, granulocytes, and B and T cells, showed a similar defect. We also observed a direct correlation between circulating dehydroepiandrosterone (DHEA) and RACK-1 expression in leukocytes (Spearman correlation, r=0.388, P=0.001). Furthermore, in vitro treatment with DHEA resulted in increased RACK-1 expression in leukocytes and lymphocyte proliferation, confirming the role of this hormone in the modulation of its expression and immune functions. A relevant consequence of RACK-1-reduced expression was the observation that release of tumor necrosis factor alpha following lipopolysaccharide challenge and mitogen-induced lymphocye proliferation, which involves PKC-beta activation, was significantly reduced in elderly subjects. Overall, our findings contribute to the understanding of the complex process of immunosenescence and identify age-related loss in immunological responses as partially associated with decreased RACK-1 expression.