Recent reports on aging have revealed that many genetic loci affecting life span are closely linked to the machinery either producing or defending oxidative stress. Protective mechanisms against oxidative stress are thus important in countering the aging process. Thioredoxin (TRX) is a small thiol-mediated protein with a redox-active disulfide/dithiol within the conserved active site. TRX transgenic mice are more resistant than control mice to a variety of oxidative stresses including infection and inflammation. Moreover, we observed that the median life span of TRX tg mice was extended up to 135% compared to that of controls. TRX binding protein-2 (TBP-2), which is identical to vitamin D3 upregulated protein 1 (VDUP1), was identified as a binding molecule to TRX, and a negative regulator of TRX function. The expression of TBP-2/VDUP1 is frequently lost in tumor tissue and cell lines, and ectopic expression of TBP-2/VDUP1 suppresses cellular proliferation along with cell cycle arrest at the G1 phase. These findings suggest that TRX and TBP-2/VDUP1 are involved not only in cytoprotective functions against oxidative stress, but also in the regulation of cellular proliferation and the aging process.