Aging of the immune system, or immunosenescence, is a complex subject best defined as a decline in cell-mediated immunity, particularly with respect to T cell function. Paradoxically with the decline in immune function is an increase in autoantibody frequency. It has been postulated that the accumulation of anamnestic cells over time and/or environmental/infectious mimics leads to the production of autoantibodies, sometimes accompanied by autoimmune disease. This specific phenotype has given rise to the concept of a specific cluster of cytokine profiles, coined an immune-risk phenotype (IRP). The IRP is likely dictated by not only cytokine production, but also defects in activation-induced cell death and also a shift in T cell subsets. These concepts are an important bridge between basic immune function and clinical immunology in the hopes for generation of effective reconstitution to improve immune function in the elderly.