The main molecular pathways of senescence, persistent DDR and Rb lead to sustained chromatin remodeling within senescent cells. This stochastic remodeling of chromatin in senescent cells most likely facilitates promiscuous gene expression associated with cell senescence. Promiscuous gene expression refers to changes in gene expression not normally associated with non- senescent counterparts of the same cell type. Promiscuous gene expression is often observed in microarray data and other analysis of gene expression of senescent verses their non- senescent counterparts and appears to also be cell-type specific. It is hypothesised that chromatin rearrangement would allow access to DNA normally tightly packed and restrict other areas of chromatin that are normally open. It has also been suggested that DNA damage may modulate gene expression by altering the binding capacity of transcription factors. In addition, changes in DNA methylation associated with cell senescence may also contribute to promiscuous gene expression. Therefore, genes that may normally be expressed can be suppressed and genes normally suppressed become expressed.
A negative consequence of promiscuous gene expression in senescent cells is impairment in cellular function, the inability of cells to carry out their designated normal processes. As a result, the accumulation of these dysfunctional cells most likely leads to tissue dysfunction which compromises tissue structure and function, promoting disease. For example, a study using Klotho-deficient mice, which exhibit an accelerated ageing-like phenotype, investigated whether preventing cell senescence improves health-span in these mice. Plasminogen activator inhibitor-1 (PAI-1) is elevated in Klotho- deficient mice and is a known regulator of cell senescence. Klotho-deficient mice deficient in PAI-1 was reported to delay the induction of cell senescence, extending median lifespan and preserving organ structure and function. Another example of senescent cells that can no longer undertake their normal function might include senescent pancreatic beta cells that have impaired insulin release during diabetes and senescent vascular endothelial cells that display decreased activity of nitric oxide synthase (NOS). NOS is important for the production of nitric oxide (NO) required for maintaining vascular homeostasis and a decrease in NO production is associated with increased risk of cardiovascular disease. Therefore, a better understanding of the differences in the phenotype of senescent cells of different cell-types in relation to their in vivo function, is required to better understand mechanisms of disease development.
PAI-1–regulated extracellular proteolysis governs senescence and survival in Klotho mice