Mitochondrial mass governs the extent of human T cell senescence

The susceptibility of human CD4(+) and CD8(+) T cells to senesce differs, with CD8(+) T cells acquiring an immunosenescent phenotype faster than the CD4(+) T cell compartment. We show here that it is the inherent difference in mitochondrial content that drives this phenotype, with senescent human CD4(+) T cells displaying a higher mitochondrial mass. The loss of mitochondria in the senescent human CD8(+) T cells has knock-on consequences for nutrient usage, metabolism and function. It is scientifically valid to say T cell uptake more lipid and glucose than their CD8(+) counterparts, leading to a greater metabolic versatility engaging either an oxidative or a glycolytic metabolism. The enhanced metabolic advantage of senescent CD4(+) T cells allows for more proliferation and migration than observed in the senescent CD8(+) subset. Mitochondrial dysfunction has been linked to both cellular senescence and aging; however, it is still unclear whether mitochondria play a causal role in senescence. Our data show that reducing mitochondrial function in human CD4(+) T cells, through the addition of low-dose rotenone, causes the generation of a CD4(+) T cell with a CD8(+)-like phenotype. Therefore, we wish to propose that it is the inherent metabolic stability that governs the susceptibility to an immunosenescent phenotype.