High-affinity Na-dependent dicarboxylate cotransporter promotes cellular senescence by inhibiting SIRT1

High-affinity Na⁺-dependent dicarboxylate cotransporter (NaDC3) can transport Krebs cycle intermediates into cells. Our previous study has shown that NaDC3 promotes cellular senescence, but its mechanism is not clear. It is known that when the concentration of intermediates in Krebs cycle is increased, NAD⁺/NADH ratio will be decreased. NAD⁺-dependent histone deacetylase sirtuin1 (SIRT1) prolongs mammalian cellular lifespan. Therefore, we propose that NaDC3 accelerates cellular aging by inhibiting SIRT1. After NaDC3 was overexpressed in two human embryo lung fibroblastic cell lines, WI38 and MRC-5, we found that the cells displayed aging-related phenotypes in advance. Meanwhile, the level of SIRT1 activity was down-regulated. In WI38/hNaDC3 cells treated with the activators of SIRT1, aging-related phenotypes induced by NaDC3 were obviously improved. The NAD⁺/NADH ratio in WI38/hNaDC3 cells was also decreased. Further study found that enhanced intracellular NAD⁺ level could attenuate the aging phenotypes induced by NaDC3. Thus, NaDC3 promotes cellular senescence probably by inhibiting NAD⁺-dependent SIRT1.