Examining the rate of in vivo T cell turnover (proliferation) in aged mice revealed a marked reduction in turnover at the level of memory-phenotype CD44(hi) CD8(+) cells relative to young mice. Based on adoptive transfer experiments, the reduced turnover of aged CD44(hi) CD8(+) cells reflected an inhibitory influence of the aged host environment. Aged CD44(hi) CD8(+) cells also showed poor in vivo responses to IL-15 and IL-15-inducing agents, but responded well to IL-15 in vitro. Two mechanisms could account for the reduced turnover of aged CD44(hi) CD8(+) cells in vivo. First, aging was associated with a prominent and selective increase in Bcl-2 expression in CD44(hi) CD8(+) cells. Hence, the reduced turnover of aged CD44(hi) CD8(+) cells may in part reflect the antiproliferative effect of enhanced Bcl-2 expression. Second, the impaired in vivo response of aged CD44(hi) CD8(+) cells to IL-15 correlated with increased serum levels of type I interferons (IFN-I) and was largely reversed by injection of anti-IFN-I antibody. Hence the selective reduction in the turnover of aged CD44(hi) CD8(+) cells in vivo may reflect the combined inhibitory effects of enhanced Bcl-2 expression and high IFN-I levels.