To investigate the beneficial effects of food restriction on systemic lupus erythematosus in NZB x NZW F1 mice, we separated the mice into three groups. One was fed a diet in which total food intake was reduced to 60% of normal from age 2 mo onward, while the animals were still healthy (group 2R). A second group was selected at age 7 mo based on a positive lupus nephritis (proteinuria) and fed the 40% restricted diet thereafter (group 7R); a third group was allowed to consume food ad libitum (control). All control mice died of renal disease by age 14 mo, whereas all mice in group 2R and 80% of those in group 7R were living at that age. Measurements of anti-double stranded DNA antibody concentrations in sera and in supernatants of in vitro spleen cell cultures revealed that the production of the immunoglobulin G, but not immunoglobulin M, class of antibodies was markedly and significantly reduced in food-restricted mice. Age-associated changes in lymphocyte subsets seen in control mice, i.e., increases in B:T and CD4:CD8 T cell ratios, decreases in NTA260+ T cell subsets, and increases in aberrant activated NTA204+CD4+ T cells and cycling cells, were all significantly lessened in underfed mice. Food restriction did not suppress the secondary acquired antibody responses to a foreign antigen. Thus, the beneficial effects of food restriction in these mice may be related to the lessening of the age-related onset of T cell subset abnormalities, including activation of autoreactive T cells.(ABSTRACT TRUNCATED AT 250 WORDS)