A Look at the Signaling that Produces Bystander Senescence
The burden of senescent cells in tissues throughout the body increases with age, as the immune system becomes ever less capable of clearing such cells in a timely fashion. Senescent cells do not replicate, but instead devote their energies to the production of pro-growth, pro-inflammatory signaling that is disruptive to tissue structure and function when maintained for the long term. These cells actively contribute to degenerative aging in this way. Senescent cells are not just produced by reaching the Hayflick limit, or by damage of some sort. They can also become senescent in response to the signaling of other senescent cells, or via other forms of stress signaling that are far from fully understood at this time. Researchers here delve into what is know of the signaling that can produce what is known as bystander senescence.
Current data suggest that senescence is neither entirely intrinsic nor simply time-dependent. Certain soluble elements present in the systemic milieu - proteins, lipids, and reactive oxygen species (ROS) - can induce bystander senescence, but there are likely others, as yet unidentified, that are also capable of accomplishing this result, either individually or in combination. Extracellular vesicles (EVs) can induce bystander senescence, but only a few components of these vesicles that are responsible for this result are specifically known. Many of these components are microRNAs (miRNAs); however, hundreds of miRNAs have been identified, and we still have much to learn about their functions. Whether nuclear DNA or mitochondrial DNA in apoptotic bodies contributes to senescence in the healthy cells that engulf them is a tantalizingly unexplored frontier. The same is true for non-vesicular multi-component macromolecules that are known to be taken up by non-senescent cells. Our knowledge of the systemic components that provoke senescence in healthy cells remains incomplete, and the importance of this paradigm demands further investigation.
The characterization of age-altered contents - proteins, lipids, and nucleic acids - of vesicles and aggregates, as well as the identification of the senescent cells that release them and the mechanisms of their uptake, is an enormous but essential endeavor. A deeper understanding of this field will be invaluable to the development of senolytics that can prevent an organism-wide loss of health due to the propagation of senescence from a pathological tissue to healthier tissues. Notably, it is important to confirm the many in vitro studies using in vivo paradigms. In vivo studies will not only confirm the physiological relevance of senescence but also provide insights into whether senescence is induced directly by interactions between the inducing factor and the target cell or mediated indirectly by other cell types (e.g., macrophages and microglia) whose secretions may change when they are affected by the inducing factor. Moreover, it is necessary to employ multiple assays to reach reliable conclusions. When asserting that a cell is senescent, for example, this should be demonstrated by morphology, a lack of proliferation, an increase in cyclin-dependent kinase inhibitor production, senescence-assocated-β-gal, phosphorylated histone γH2AX, and a change in secretions, or a comparable set of assays appropriate to the cell type and senescence classification. Armed with such information, we should be able to develop new strategies that will inform us regarding physiological senescence, helping to ameliorate the adverse systemic effects of damaged tissues on an organism.