12443 Thioredoxin Interacting Protein (Txnip) Regulates Cellular Senescence And Lifespan

Abstract Disclosure: M. Abubaker: None. L. Xia: None. I.G. Fantus: None. Thioredoxin-interacting protein (Txnip) is a ubiquitously expressed protein that belongs to the α-arrestin family. It is unique among α-arrestin proteins in its ability to bind and inhibit thioredoxin (Trx), a major endogenous antioxidant. In the context of diabetes, hyperglycemia upregulates Txnip, which in turn promotes oxidative stress and apoptosis, and has been associated with progression of diabetes and its microvascular complications. Paradoxically, TXNIP also acts as a tumor suppressor, as evidenced by the development of hepatocellular carcinoma in Txnip knockout (KO) mice. Loss of Txnip is associated with enhanced glucose uptake but a shift in cellular metabolism towards glycolysis and lactate accumulation reminiscent of the Warburg effect seen in cancer cells. In our studies of glomerular mesangial cells (MC) we observed that late-passage cells (25 passages) exhibited significantly reduced Txnip expression (p<0.05) coinciding with the development of senescence, consistent with “replicative” senescence. To explore the role of Txnip, we compared primary mouse MC obtained from wild-type (WT) and Txnip KO mice at early passages (5-7). Txnip KO MCs displayed significantly increased expression of senescence markers P53 and P16, as well as enhanced senescence-associated beta-galactosidase staining (p<0.05), confirmed in kidney cortex of KO mice. Txnip KO MCs exhibited higher activation of Akt associated with lower PTEN activity compared to WT. Activation of Akt is known to stimulate the generation of reactive oxygen species (ROS). ROS (DCF fluorescence) were significantly elevated in Txnip KO MCs (p<0.05). While mitochondrial ROS generation (mitosox) was not altered, there was an increase in the expression of NADPH oxidase 4 (NOX4). Additionally, Txnip KO MCs showed increased activation of the oncogene RAS and reduced apoptosis. Inhibition of Akt rescued the senescence phenotype in Txnip KO MCs, accompanied by reduced total ROS and NOX4 expression. Accumulation of senescent cells is a hallmark of organismal aging. Using a Y-maze apparatus, we assessed spatial memory in 21-month-old mice. KO mice exhibited compromised memory function compared to their WT counterparts. Significantly, Txnip KO mice, male and female, showed a shortened lifespan (median WT 28 m; KO 20.3 m; and Maximum WT 38 m; KO 29.5 m; Kaplan-Meier p<0.001) and increased susceptibility to tumor growth at later ages. Our findings demonstrate for the first time that loss of Txnip contributes to cellular senescence through mechanisms consistent with oncogene-induced senescence, including increased Akt and RAS activation. These findings highlight the potential importance of Txnip in age-related diseases and tumorigenesis. Considering Txnip as a potential therapeutic target in diabetes, our data emphasize caution since overexpression and under-expression of TXNIP can both have adverse health consequences. Presentation: 6/3/2024