Now that the accumulation of senescent cells is broadly accepted to be one of the fundamental causes of aging, ever greater funding is flowing into this part of the scientific ecosystem. Many research groups are investigating aspects of the biochemistry of cellular senescence: how cells become senescent; the harmful signaling they produce; ways to prompt them to self-destruct, thereby removing their contribution to the aging process. One of the results of this expansion of effort is that some proteins previously known to be associated with aging are now being found to either influence or act through cellular senescence. The research here is an interesting example of the type, in which TXNIP, a protein associated with oxidative stress and aging in flies, is now implicated in cellular senescence in mice.
Cells are constantly exposed to metabolic stress, a major cause of cellular senescence. Recent reports have shown that metabolic changes influence aging in model systems, from the budding yeast to mouse models. One of the prominent cellular senescence markers is the accumulation of reactive molecules, such as reactive oxygen species (ROS), a product of an essential energy production. Glucose serves as an energy source in virtually all eukaryotic cells. A high concentration of glucose increases the metabolic input into cells and consequently induces oxidative stress via ROS production, thereby inducing DNA, protein, and lipid damage, causing premature senescence.
Thioredoxin-interacting protein (TXNIP) is an α-arrestin family protein that is induced by a rise in glucose and oxidative stress and is known to be a tumor suppressor and inhibit thioredoxin (TRX), an antioxidant protein, via a direct interaction. Many studies have examined the role of TXNIP in glucose uptake and metabolism. TXNIP expression is related to mitochondrial fuel switching under conditions of starvation, diabetes, and exercise in skeletal muscle. Previously, we suggested that TXNIP is highly expressed and acts as an antioxidant protein to regulate cellular ROS by activating p53 activity or by inhibiting p38 mitogen-activated protein kinase (MAPK) activity.
AKT is a serine-threonine kinase that is involved in a variety of cellular processes including cell survival, proliferation, and metabolism. AKT plays an essential role in the insulin-regulated transport of glucose and in whole-body glucose homeostasis. Activation of the AKT pathway is directly correlated with increased rates of glucose metabolism. The activation of AKT induces intracellular ROS by inducing oxygen consumption or inhibiting the forkhead box O (FOXO) family of transcription factors, in turn, promoting cellular senescence and apoptosis. AKT also activates the mechanistic target of rapamycin (mTOR) and induces cellular senescence.
In this study, we found that TXNIP deficiency induces accelerated senescent phenotypes of mouse embryonic fibroblast (MEF) cells under high glucose condition and that the induction of cellular ROS or AKT activation is critical for cellular senescence. Our results also revealed that TXNIP inhibits AKT activity by a direct interaction, which is upregulated by high glucose and H2O2 treatment. In addition, TXNIP knockout mice exhibited an increase in glucose uptake and aging-associated phenotypes including a decrease in energy metabolism and induction of cellular senescence and aging-associated gene expression. We propose that TXNIP is a critical regulator of AKT-mediated cellular senescence under glucose-mediated stress in vitro and in vivo.