Biomarkers of aging: prediction of longevity by using age-sensitive T-cell subset determinations in a middle-aged, genetically heterogeneous mouse population

Abstract

Seven T-cell subset values were measured in each of 559 mice at 8 months of age, and then again in the 494 animals that reached 18 months of age. The group included virgin males, virgin females, and mated females, and it was produced by using a four-way cross-breeding system that generates genetic heterogeneity equivalent to a very large sibship. An analysis of covariance showed that four T-cell subsets-CD4, CD4 memory, CD4 naïve, and CD4 cells expressing P:-glycoprotein-were significant predictors (p <.003) of longevity when measured at 18 months of age after adjustment for the possible effects of gender and mating. The subset marked by CD4 and P:-glycoprotein expression showed a significant interaction effect: this subset predicted longevity only in males. Among subsets measured when the mice were 8 months of age, only the levels of CD8 memory cells predicted longevity (p =.016); the prognostic value of this subset was largely limited to mated females. A cluster analysis that separated mice into two groups based upon similarity of T-cell subset patterns measured at 18 months showed that these two groups differed in life expectancy. Specifically, mice characterized by relatively low levels of CD4 and CD8 memory cells, high levels of CD4 naïve cells, and low levels of CD4 cells with P:-glycoprotein (64% of the total) lived significantly longer (50 days = 6%; p <.0007) than mice in the other cluster. The results are consistent with the hypothesis that patterns of T-cell subsets vary among mice in a manner than can predict longevity in middle age, and they suggest that these subsets may prove to be useful for further studies of the genetics of aging and age-sensitive traits.

Figure 1.

Selected scatterplots showing longevity as a function of T-cell subset values measured when the mice were 18 months of age: ▴, data from virgin males; •, virgin females; ○, mated females. Lines were calculated by least-squares regression for all mice combined, except that separate lines are shown for the CD4P scatterplot, for which a regression analysis revealed a significant interaction with group.

Figure 2.

Scatterplot showing longevity related to CD8M values measured when the mice were 8 months of age. Symbols are the same as in Fig. 1. A separate regression line is shown for each group of mice; the arrow indicates the group (mated females) with the strongest association between CD8M and life span.

Figure 3.

Cluster analysis using data from 18-month-old mice. The left panel shows mean values (±SEM) for each subset in the two clusters defined by a k-means clustering algorithm based on subset data alone; the right panel presents mean longevity (±SEM) for mice in each of the two clusters, first for all mice (left pair of bars), and then separately for the three groups.