Cellular and biochemical changes in the aging mouse immune system.

My perspective is different from that of Dr. Weksler. I see age-related loss of responsiveness as a cardinal feature of immunosenescence, one that puts elderly people at risk of infection and perhaps neoplasia. It is possible that age-associated increases in the activity of some kinds of immune cells, which Dr. Weksler has emphasized, contribute to this decline in protective immunity, although this hypothesis needs a good deal of further investigation. I do not see autoimmunity as a major threat to the elderly or an important component of immunosenescence, although the jury is still out on this, and clearly investigators of autoreactivity have the potential for teaching us a lot about how the aged immune system works. Thus in my view one of the most pressing challenges for immunogerontologists is to figure out why the immune system generates fewer antibodies to specific antigens, fewer cytotoxic T cell effectors, and less protection against potential infections and pathologic agents in elderly humans and old mice. I will call this deficiency of function, and I think that some of the cross-wiring that Dr. Weksler and others have pointed out may give us a way of exploring it anew. I am not convinced by arguments to date that have suggested an important pathological implication for autoimmunity. Some autoimmune phenomena are demonstrated in elderly mice and humans, but their pathological implications are still mysterious; more work needs to be done to understand the implications for health and disease. The cellular and molecular basis for the agerelated decline in immune responsiveness can be enumerated in several ways. First, there is an agerelated change in T cell subsets. Figure I shows that there is an age-associated accumulation of memory (Pgp-lhi) T'cells. There is a decrease with age in the number of virgin T lymphocytes resulting in a relatively greater proportion of memory as com-