Evolutionarily Conserved Role of Thioredoxin Systems in Determining Longevity

Abstract

Thioredoxin and thioredoxin reductase are evolutionarily conserved antioxidant enzymes that protect organisms from oxidative stress. These proteins also play roles in redox signaling and can act as a redox-independent cellular chaperone. In most organisms, there is a cytoplasmic and mitochondrial thioredoxin system. A number of studies have examined the role of thioredoxin and thioredoxin reductase in determining longevity. Disruption of either thioredoxin or thioredoxin reductase is sufficient to shorten lifespan in model organisms including yeast, worms, flies and mice, thereby indicating conservation across species. Similarly, increasing the expression of thioredoxin or thioredoxin reductase can extend longevity in multiple model organisms. In humans, there is an association between a specific genetic variant of thioredoxin reductase and lifespan. Overall, the cytoplasmic and mitochondrial thioredoxin systems are both important for longevity.

Thioredoxin (Trx): A redox target and modulator of cellular senescence and aging-related diseases

“…Trx plays a crucial role in regulating the redox balance of antioxidant enzymes by enhancing their catalytic activity. This enhancement enables them to efficiently detoxify ROS and protect senescent cells from oxidative stress [ 178 ]. Additionally, Trx exhibits interaction with the transcription factor Nrf2, which governs the expression of genes involved in antioxidation [ 178 ].…”

“…This enhancement enables them to efficiently detoxify ROS and protect senescent cells from oxidative stress [ 178 ]. Additionally, Trx exhibits interaction with the transcription factor Nrf2, which governs the expression of genes involved in antioxidation [ 178 ]. By reducing cysteine residues on Nrf2, Trx promotes its dissociation from Kelch-like ECH-associated protein 1 (Keap1), a negative regulator that sequesters Nrf2 within the cytoplasm [ 179 ].…”

“…This may involve complex interactions between Trx and various redox signaling pathways, as well as Trx direct involvement in stress response cascades related to longevity mechanisms, such as mitochondrial unfolded protein response (mitoUPR), hypoxia response, and apoptosis pathway regulation. Studies have shown that mild stress caused by mitochondrial damage can extend the lifespan of genetic model organisms (such as worms, flies, and mice) [ 178 ]. Namastheé et al further demonstrated that longevity is mediated by gene-specific upregulation of Trx in long-lived mitochondria, which is triggered by mitoUPR caused by mild mitochondrial damage [ 275 ].…”

Use of Viscous medium to study anthelmintic drug action in Caenorhabditis elegans

“…The development curve for NGM agar was not able to reach a 0% development stage due to lack of solubility of albendazole in DMSO for the stock solution and for the serial dilution in agar. More DMSO could not be added to the wells as DMSO concentrations higher than 1% would inhibit worm development 38 .…”

The Drosophila cancer-germline, head-to-head gene pairTrxTanddhdis dispensable for normal brain development but plays a major role inl(3)malignant brain tumourgrowth

“…According to Flybase (Gramates et al, 2022), the Drosophila thioredoxin group includes 9 proteins out of which Dhd, TrxT, Trx-2 and Txl contain the classical thioredoxin motif WCGPCK (AlOkda and Van Raamsdonk, 2023;Mondal and Singh, 2022;Svensson and Larsson, 2007). Trx-2, which is ubiquitously expressed, is the orthologue of human TXN that is found at elevated levels in many cancer types and plays an important role in tumour progression and metastasis (Arner and Holmgren, 2006;Flores et al, 2012;Karlenius and Tonissen, 2010).…”