Cellular redoxbalance is maintained by various antioxidative systems among those is the thioredoxin system consisting of thioredoxin, thioredoxin reductase and NADPH. In the present study, we examined the effects of caloric restriction (2 months) on the expression of the cytosolic and mitochondrial thioredoxin system in skeletal muscle and heart of senescent and young rats. Mitochondrial thioredoxin reductase (TrxR2) is significantly reduced in aging skeletal and cardiac muscle and renormalized after caloric restriction, while the cytosolic isoform remains unchanged. Thioredoxins (mitochondrial Trx2, cytosolic Trx1) are not influenced by caloric restriction. In skeletal and cardiac muscle of young rats, caloric restriction has no effect on the expression of thioredoxins or thioredoxin reductases. Enforced reduction of TrxR2 (siRNA) in myoblasts under exposure to ceramide or TNF-alpha causes a dramatic enhancement of nucleosomal DNA-cleavage, caspase 9 activation and mitochondrial ROS release together with reduced cell viability, while this TrxR2 reduction is without effect in unstimulated myoblasts under basal conditions. Oxidative stress in vitro (H₂O₂ in C2C12 myoblasts und myotubes) results in different changes: TrxR2, Trx2 and Trx1 are induced without alterations in the cytosolic thioredoxin reductase isoforms. Thus, aging is associated with a TrxR2 reduction in skeletal muscle and heart which enhances susceptibility to apoptotic stimuli but is renormalized after short-term caloric restriction. Exogenous oxidative stress does not result in these age-related changes of TrxR2.