A rising level of TGF-β has long been associated with numerous aspects of aging. More modern research has shown it to encourage cells to become senescent. Further, TGF-β is an important component of the inflammatory mix of signals secreted by senescent cells, making it a part of the mechanism by which senescent cells can encourage their neighbors to also become senescent. When senescent cells fail to clear quickly, as happens in older individuals, this leads to a feedback loop of continually rising chronic inflammation and ever greater numbers of senescent cells. This is an important contribution to degenerative aging and the progressive failure of tissue and organ function throughout the body.
TGF-β exerts diverse functions by modulating the expression of downstream target genes via transcriptional and post-transcriptional mechanisms as well as protein modulation in a context-dependent manner. Importantly, the downstream targets of TGF-β signaling include many regulators involved in multiple aspects of aging processes, such as cell proliferation, cell cycle regulation, the production of reactive oxygen species (ROS), DNA damage repair, telomere regulation, unfolded protein response (UPR), and autophagy. Due to a large overlap between the two pathways, TGF-β signaling exhibits multifaceted crosstalk with aging processes. At the cellular level, TGF-β signaling has been shown to play an important role in cellular senescence and stem cell aging. Furthermore, the alteration of TGF-β signaling pathways has been frequently observed in various age-related diseases, including cardiovascular disease, Alzheimer's disease (AD), osteoarthritis, and obesity.
TGF-β has been shown to have dual functions in cancer biology: An early tumor suppressor and a late tumor promoter. The cytostatic effects of TGF-β are mediated by inducing the cyclin-dependent kinase inhibitors p15Ink4b, p21, and p27, and by suppressing several proliferation factors including c-Myc. This suggests a senescence promoting role of TGF-β under normal conditions and also coincides with the tumor suppressing role of cell senescence. TGF-β has been shown to induce or accelerate senescence and senescence-associated features in various cell types. In addition, the TGF-β-mediated accumulation of senescent cells has been suggested in idiopathic pulmonary fibrosis (IPF).
In addition to the cytostatic mechanisms, the senescence-promoting role of TGF-β might be explained by the effects on other modulators of senescent phenotypes. TGF-β reportedly induces ROS production in the mitochondria in several cell types. In addition, TGF-β suppresses telomerase activities by downregulating the expression of telomerase reverse transcriptase (TERT) in various cell types. Further, the senescence-associated secretory phenotype (SASP) yields the production and secretion of various signaling molecules, importantly including TGF-β. Thus, TGF-β is secreted as one of the SASP factors and can induce and maintain senescent phenotype and age-related pathological conditions in an autocrine/paracrine manner.