CD4 memory T cell levels predict life span in genetically heterogeneous mice

Aging leads to changes in the relative proportions of several functionally distinct T cell subsets, including increases in the proportions of memory cells in the CD4 and CD8 subsets and in the proportion of T cells expressing the multiple-drug resistance pump P-glycoprotein. To see whether individual differences in T cell subset levels predict life span, we measured the levels of five age-sensitive T cell subsets, at 8 and again at 18 months of age, in the peripheral blood of genetically heterogeneous mice bred as the progeny of CB6F1 females and C3D2F1 males. The strongest immunological predictor of life span in univariate regression analyses was the proportion of CD4 memory cells measured at 18 months of age (P=0.003). CD4 memory cell levels remained strongly correlated with life span (P<0.0003) in a multiple regression analysis after adjustment for sex. The proportion of CD4 cells expressing P-glycoprotein was also correlated with life span (P<0.01), but only in male mice. Weaker relationships were observed between life span and 8-month tests of CD8 memory and CD8 P-glycoprotein levels, for CD4 naive cells at 18 months, and for the change in CD4 naive cells between 8 and 18 months of age; these were, however, near the margin of statistical significance and could reflect chance relationships. The relationship between CD4 memory cell levels and life span was similarly strong regardless of the cause of death in mice whose death was attributable to lymphoma, fibrosarcoma, mammary carcinoma, and other forms of terminal pathology. Additional work is needed to discriminate between two hypotheses: 1) that high levels of CD4 memory cell themselves predispose to disease and early death, particularly from neoplasia; or 2) that accumulation of CD4 memory cells is a biomarker of some underlying process-perhaps accelerated aging-that itself leads to early mortality.