Impaired signal transduction in mitogen activated rat splenic lymphocytes during aging

Mitogen activated protein kinases (MAPK) are activated by a wide variety of signals leading to cell proliferation and differentiation in different cel l types. With aging, there is a marked decrease in proliferation of T-lymph ocytes in response to a variety of mitogens, Several age-related changes in the activation of MAPK pathways in T-lymphocytes activated via the T-cell receptor (TCR) have been described in different species. This way, some TCR proximal defects in tyrosine kinase activity have been delineated. In this study, we have used rat splenic lymphocytes to measure the effect of aging on the activation of two MAP kinase families: ERK and JNK. In order to byp ass the receptor-proximal age-dependent defects previously described, we us ed phorbol ester (PMA) and Ca2+ ionophore (A23187) as co-mitogens. Our resu lts demonstrate that splenic lymphocytes from old rats have a disturbance i n the activation of the ERK and JNK MAPK signal transduction pathways, that are located downstream of the receptor-proximal events. At least part of t he age-related defect leading to decreased ERK activity appears to be locat ed upstream of ERK itself, since activation of MEK is also impaired. On the other hand, the observed defects in MAPK activation do result in decreased activation of downstream events, such as c-Jun phosphorylation. Thus, we c onclude that aging of splenic lymphocytes results in a functional decline i n signal transduction, and at least some of these defects are located downs tream of the receptor-proximal events previously described by others. The i mpaired activity of these two MAP kinase pathways is likely to play a role in the diminished lymphoproliferation observed in old individuals. (C) 2000 Published by Elsevier Science Ireland Ltd. All rights reserved.