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

Abstract

Thioredoxin (Trx) is a compact redox-regulatory protein that modulates cellular redox state by reducing oxidized proteins. Trx exhibits dual functionality as an antioxidant and a cofactor for diverse enzymes and transcription factors, thereby exerting influence over their activity and function. Trx has emerged as a pivotal biomarker for various diseases, particularly those associated with oxidative stress, inflammation, and aging. Recent clinical investigations have underscored the significance of Trx in disease diagnosis, treatment, and mechanistic elucidation. Despite its paramount importance, the intricate interplay between Trx and cellular senescence-a condition characterized by irreversible growth arrest induced by multiple aging stimuli-remains inadequately understood. In this review, our objective is to present a comprehensive and up-to-date overview of the structure and function of Trx, its involvement in redox signaling pathways and cellular senescence, its association with aging and age-related diseases, as well as its potential as a therapeutic target. Our review aims to elucidate the novel and extensive role of Trx in senescence while highlighting its implications for aging and age-related diseases.

Keywords: Age-related diseases; Anti-oxidative; Cellular senescence; ROS; Thioredoxin.

Graphical abstract

Fig. 1

Thioredoxin redox cycle. The figure illustrates the subcellular localization, structural features, and functional aspects of TRX and TRXR, along with the regulatory interaction between TRX and TXNIP during oxidative stress. The left panel of the figure presents a schematic representation while the right panel depicts a surface model of these proteins. The oxidized and reduced states of TRX are denoted by red and blue colors correspondingly. Notably, the active site of TRX encompasses a Cys-Gly-Pro-Cys (CGPC) motif that facilitates electron transfer to target proteins. As for TRXR, it exists as a homodimer utilizing NADPH as an electron donor to catalyze the reduction of TRX. In addition to its inhibitory effect on TRX activity and expression through binding interactions, TXNIP also plays diverse roles in cellular stress response including activation of inflammation, apoptosis, and cell death pathways. Furthermore, TXNIP is subject to regulation by various factors such as glucose levels, reactive oxygen species (ROS), and cytokines. Importantly, TXNIP exhibits distinct subcellular compartmentalization with potential interactions with TRX occurring within cytosol, mitochondria, or nucleus compartments. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2

Trx's impact on cell senescence initiation. The provided figure demonstrates the modulation of cell senescence initiation by TRX through its regulation of various proteins and pathways involved in cellular growth, survival, and stress response. The figure is divided into seven sections, each highlighting a distinct aspect of TRX regulation. It effectively portrays both the positive and negative impacts of TRX on these proteins and pathways, while also showcasing the feedback loops and cross-talks between them. For detailed regulatory pathways, please refer to the accompanying text.

Fig. 3

How Trx Influences Cell Senescence maintenance. The figure depicts the molecular mechanisms through which TRX exerts its influence on cell senescence maintenance. Specifically, TRX can modulate the activity and expression of CDKs and CKIs(a), which are pivotal regulators of cell cycle progression and senescence. Additionally, TRX can impact cytoskeleton dynamics(b) as well as the AMPK(c) signaling pathway that governs cellular metabolism and energy homeostasis. Furthermore, by regulating ROS levels and antioxidant enzymes(d), TRX is capable of modulating the oxidative stress response pathway - a major trigger for senescence. Moreover, TRX interacts with critical Rb/E2F(e) and mTOR(f) signaling pathways that regulate cell growth and proliferation; thus, depending on cellular context, it may either promote or inhibit cell senescence. The specific regulatory pathways are elaborated in detail within the text.

Fig. 4

Cellular senescence regulates TRX proteins through various pathways and at different levels. The diagram depicts the impact of cellular senescence on the expression and functionality of TRX proteins, which play a crucial role in redox regulation and anti-aging processes. Various stimuli, including oxidative stress, DNA damage, telomere shortening, and inflammatory response can induce cellular senescence.(a) These stimuli exert their influence on TRX protein levels through distinct mechanisms at four different levels: epigenetics, transcriptional regulation, post-translational modification, and proteolysis.(b) The figure provides illustrative examples for each mechanism elucidating how they modulate the activity and stability of TRX proteins. Additionally, it highlights the existence of feedback loops between TRX proteins and cellular senescence. Detailed information regarding these specific regulatory pathways is presented in the main text to ensure a comprehensive understanding.

Fig. 5

Abnormal Trx system causes aging-related diseases by regulating cellular senescence. The Trx system mainly consists of three components, Trx, TrxR and TXNIP. Cancer, diabetes, cardiovascular disease, and neurological disease are four of the most common aging-related diseases. When the Trx system becomes abnormal, which can be caused by exogenous factors or by cellular anti-aging stress, it may lead to changes in the cellular senescence process, thereby increasing the susceptibility to various aging-related diseases. For cancer, ND, and CVD, we list the pathogenesis mechanisms involving Trx regulation. For diabetes, we list some of its major complications.

Fig. 6

The role of Trx system-regulated redox state in the progression of aging-related diseases. The figure shows the changes in the levels of functional Trx (reduced Trx) and oxidative stress in the cells with the progression of the disease. (a) CA: In the process of cancer progression, from normal cells to cancer cells, there is usually an increase in the level of oxidative stress, accompanied by the activation of oncogenes and the inactivation of tumor suppressor genes. In the further development of cancer, oxidative stress accumulates further. When the level of oxidative stress is low, the level of reduced Trx increases to counteract the excess oxidative stress. This process will promote cancer progression, including angiogenesis, immune escape, drug resistance, and cell proliferation. When the level of oxidative stress exceeds the compensation limit of the Trx system due to exogenous or endogenous factors, reduced Trx will be more converted to oxidized Trx and lose function, leading to senescence and apoptosis of cancer cells. (b) NDs: In neurodegenerative diseases, neuronal senescence occurs early, and oxidative stress, Aβ aggregation, and neuroinflammation initiate cellular senescence. At this time, the level of reduced Trx compensatorily increases to prevent the initiation or further progression of cellular senescence. In the end stage of the disease, TXNIP upregulation and excessive oxidative stress in the cells lead to further aggravated inflammation and reduced Trx. (c) CVDs: Most heart diseases go through the process from initial ischemic injury to heart failure, which we take as an example. Due to ischemia and hypoxia, the level of oxidative stress increases and causes ischemic injury to the heart. At this moment, the compensatory increase of the Trx system can inhibit this process. However, when there are endogenous or exogenous factors that cause Trx system imbalance, it will lead to an increased risk of heart disease progression. Mitochondria and inflammatory response are two major influencing factors. (d) Diabetes: The disease progression of diabetes is often assessed by the occurrence of complications. Early on, oxidative stress-induced β-cell damage can induce diabetes. The Trx system can inhibit the progression of this process. However, under high glucose conditions, oxidative stress accumulation and inflammation upregulation are more likely to occur. This leads to further progression of diabetes and induces various complications.

Fig. 7

Drug development of Trx system targeting drugs. Screening based on natural products, computer-aided drug design, and chemical synthesis (nanomedicine technology) are the main strategies for developing Trx system targeting drugs. The drugs currently studied include natural products, synthetic compounds, nanomedicine systems, recombinant proteins, and so on. In terms of treatment, cancer and the other three aging-related diseases have different characteristics. In cancer, we need to inhibit the antioxidant function of the Trx system to cause senescence and death of cancer cells. In the prevention and treatment of NDs, CVDs, diabetes and its complications, we need to protect the antioxidant function of the Trx system to prevent the initiation of cellular senescence.