It is satisfying to see long-standing areas of metabolism-focused aging research find connections to forms of cell and tissue damage thought to drive aging. A great deal of effort has gone towards characterizing growth hormone and IGF1 signaling in aging, as manipulating this part of cellular metabolism has been shown to slow aging in mice. The human population with loss of function in growth hormone receptor, producing Laron syndrome, is the subject of analogous studies. Here, researchers report on evidence for IGF1 stimulation to produce a greater burden of cellular senescence, a possibly important mechanism to explain why reduced IGF1 signaling can slow aging in laboratory animals. Senescent cells, when they linger in increasing numbers with age, produce inflammatory signaling that actively harms tissue structure and function.
The growth hormone (GH)-insulin-like growth factor-1 (IGF1) signaling pathway plays a major role in orchestrating cellular interactions, metabolism, growth, and aging. Studies from worms to mice showed that downregulated activity of the GH/IGF1 pathway could be beneficial for the extension of lifespan. Laron syndrome (LS) is an inherited disorder caused by molecular defects of the GH receptor (GHR) gene, leading to congenital IGF1 deficiency. Life-long exposure to very low endogenous IGF1 levels in LS is associated with small stature as well as endocrine and metabolic deficits. Epidemiological surveys reported that patients with LS have a reduced risk of developing cancer.
Studies conducted on LS-derived cells led to the identification of a novel link between IGF1 and thioredoxin-interacting protein (TXNIP), a multifunctional mitochondrial protein. TXNIP is highly expressed in LS patients and plays a critical role in cellular redox regulation by thioredoxin. Given that IGF1 affects the levels of TXNIP under various stress conditions, including high glucose and oxidative stress, we hypothesized that the IGF1-TXNIP axis plays an essential role in helping maintain a physiological balance in cellular homeostasis.
In this study, we show that TXNIP is vital for the cell fate choice when cells are challenged by various stress signals. Furthermore, prolonged IGF1 treatment leads to the establishment of a premature senescence phenotype characterized by a unique senescence network signature. Combined IGF1/TXNIP-induced premature senescence can be associated with a typical secretory inflammatory phenotype that is mediated by STAT3/IL-1A signaling. Finally, these mechanistic insights might help with the understanding of basic aspects of IGF1-related pathologies in the clinical setting.