The major characteristics of cellular senescence are stable cell-cycle arrest, accumulation of DNA damage responses, mitochondrial dysfunction, metabolic remodeling, and the release of pro-inflammatory senescence-associated secretory phenotype (SASP) factors. Redox imbalance plays a significant role in the initiation and maintenance of senescence, and the mammalian thioredoxin system-comprising cytosolic Trx-1, mitochondrial Trx-2, thioredoxin reductases (TrxR1, TrxR2), and the inhibitor TXNIP-is at a key juncture between oxidative stress, cellular ageing, and age-related diseases. Evidence was identified through a structured literature search of PubMed, Web of Science, and Scopus from inception to July 2026 using predefined search terms and eligibility criteria. Primary experimental studies in mammalian cells, tissues, or animal models that directly measured senescence markers were prioritised. Reviews, non-mammalian studies, and studies reporting only general oxidative-stress endpoints were included only when they provided essential mechanistic context and are clearly labelled as such. This review focuses primarily on mammalian mechanisms linking the thioredoxin system to senescence initiation, senescence maintenance, inflammaging, tissue dysfunction, and translational geroscience. We distinguish isoform-specific and context-dependent effects of Trx-1, Trx-2, TrxR, and TXNIP. We also discuss therapeutic strategies targeting the thioredoxin system, including redox modulation, isoform-selective inhibitors, senomorphic approaches, and disease-specific interventions. Overall, the thioredoxin system is a significant molecular link between redox homeostasis, cellular senescence, ageing biology, and age-related pathology, and a candidate target for future geroscience interventions, although direct evidence in aged mammals remains limited.
