TGF-β as A Master Regulator of Aging-Associated Tissue Fibrosis

Abstract

Fibrosis is the abnormal accumulation of extracellular matrix proteins such as collagen and fibronectin. Aging, injury, infections, and inflammation can cause different types of tissue fibrosis. Numerous clinical investigations have shown a correlation between the degree of liver and pulmonary fibrosis in patients and telomere length and mitochondrial DNA content, both of which are signs of aging. Aging involves the gradual loss of tissue function over time, which results in the loss of homeostasis and, ultimately, an organism's fitness. A major feature of aging is the accumulation of senescent cells. Senescent cells abnormally and continuously accumulate in the late stages of life, contributing to age-related fibrosis and tissue deterioration, among other aging characteristics. Furthermore, aging generates chronic inflammation, which results in fibrosis and decreases organ function. This finding suggests that fibrosis and aging are closely related. The transforming growth factor-beta (TGF-β) superfamily plays a crucial role in the physiological and pathological processes of aging, immune regulation, atherosclerosis, and tissue fibrosis. In this review, the functions of TGF-β in normal organs, aging, and fibrotic tissues is discussed: TGF-β signalling is altered with age and is an indicator of pathology associated with tissue fibrosis. In addition, this review discusses the potential targeting of noncoding.

Figure 1.

Mechanisms of fibrosis. Aging, injury, infection, and inflammation can promote epithelial cells to myofibroblast transition, regulate ECM formation and remodelling, and ultimately lead to tissue fibrosis or efficient repair. Activated epithelial cells secrete many inflammatory mediators, such as TGF-β1 and interleukin-1β, which recruit immune cells such as mast cells, B cells, T cells, and macrophages. These invasive immune cells release TGF-β, interleukin-1β, interleukin-6, interleukin-13, and other mediators, enhancing profibrotic reactions.

Figure 2.

The role of cellular senescence in fibrosis. Cellular senescence is caused by telomere damage, epigenetic dysregulation, DNA damage, oxidative stress, mitochondrial dysfunction, proteostatic dysfunction, and mitochondrial dysfunction. Acute cellular senescence produced early in life provides a benefit during tissue fibrosis, but the aberrant and chronic accumulation of senescent cells late in life drives various features of aging, including age-related fibrosis.

Figure 3.

The TGF-β signalling pathway in aging and fibrosis. TGF-β is an inactive complex formed by the combination of TGF-β with a latency-associated peptide. Latent activation of TGF-β in fibrotic illnesses may involve ROS, aging, and integrins. NOX is one of the key enzymes linking ROS and TGF-β activity. Different NOX subtypes contribute to the production of intracellular ROS. ROS overproduction can lead to DNA damage. ROS interacts with classical and nonclassical TGF-β signalling pathways to regulate inflammation and the expression of the PAI-1, P21, fibronectin, TGF-β, and NOX4 genes. ATM, ataxia telangiectasia mutated protein; JNK, c-Jun terminal kinase; NF-κB, nuclear factor-kappa B; NOX, NADPH oxidase; PAI-1, plasminogen activator inhibitor-1; ROS, reactive oxygen species; TAK1, TGF-β-activated kinase 1; TRAF, TGF-β receptor-associated factor.