ABSTRACT
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. Senescent CD4+ T cells 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.
Subject(s)
CD8-Positive T-Lymphocytes/metabolism , Cellular Senescence/immunology , Immunosenescence/physiology , Mitochondria/metabolism , Adenosine Triphosphate/metabolism , Adult , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/physiology , CD8-Positive T-Lymphocytes/physiology , Cell Movement/immunology , Cell Proliferation/physiology , Cellular Senescence/physiology , Glucose/metabolism , Glycolysis/immunology , Humans , Leukocyte Common Antigens/blood , Leukocyte Common Antigens/metabolism , Microscopy, Electron, Transmission , Middle Aged , Mitochondria/physiology , Mitochondria/ultrastructure , Rotenone/pharmacologyABSTRACT
The impact of cellular senescence during ageing is well established, however senescence is now recognised to play a role in a variety of age related and metabolic diseases, such as cancer, autoimmune and cardiovascular diseases. It is therefore crucial to gain a better understanding of the mechanisms that control cellular senescence. In recent years our understanding of the intimate relationship between cell metabolism, cell signalling and cellular senescence has greatly improved. In this review we discuss the differing roles of glucose and protein metabolism in both senescent fibroblast and CD8+ T-cells, and explore the impact cellular metabolism has on the senescence-associated secretory phenotype (SASP) of these cell types.
