On the matter of cellular senescence as a contributing cause of degenerative aging, there is a school of thought whose members argue that at least some senescent cells are doing something useful by existing, despite their problematic behavior. Therefore therapeutic approaches should focus on prevention of senescence (senostatics) or reducing the harmful senescence-associated secretory phenotype (SASP) (senomorphics) rather than on outright destruction of senescent cells (senolytics). Within the array of possible ways to reduce the pace at which cells become senescence, sabotaging the ability of senescent cells to encourage their neighbors to also become senescent has been little explored, so it is interesting to note recent work on this topic.
Today’s open access paper represents is an early step on the path to finding ways to block bystander senescence. It is likely that the relevant interactions differ by cell type and tissue, making it a more challenging exercise than would otherwise be the case. Here, the focus is on the brain, and the researchers outline potential target interactions that might be blocked to reduce the spread of cellular senescence in an aged brain. As an approach to therapy, this does have the look of an intervention that could increase risk of cancer, however. The ability of the senescent state to spread from cell to cell is one of the ways in which early cancers are suppressed before they can become an issue. But at the end of the day, the only practical way to assess hypothetical benefits versus hypothetical risks is to build a therapy and test it in animal studies.
Characterizing the SASP-Dependent Paracrine Spreading of Senescence Between Human Brain Cell Types
One of the defining phenotypes of a senescent cell is the senescence-associated secretory phenotype (SASP), which can propagate senescence in neighboring cells both in vitro and in vivo. Importantly, this paracrine spreading of senescence can act in a cell non-autonomous manner, influencing neighboring cell populations and contributing to immune cell recruitment. As cellular senescence has recently been linked to both age-related neurodegenerative phenotypes and local inflammation and is more clearly defined across brain cell types in a cell-type-dependent manner, an urgent question remains regarding how a cell-type-specific paracrine spreading of senescence occurs in the brain.
Here, we sought to unravel the relationship between key brain cell types (astrocytes, endothelial cells, microglia, oligodendrocytes, and neurons) in the context of a paracrine spreading of senescence via the SASP. We utilized our previously established in vitro DNA damage-induced human brain cell line senescence model and conditioned media experiments to profile the cell-type-dependent SASP, characterize the directionality of a paracrine spreading of senescence between the relevant cell types, identify key SASP ligands and receptors that mediate the cell-type-specific spread, and target these factors using various inhibitors in an attempt to prevent the paracrine spreading of senescence.
We demonstrate that a cell-type-specific SASP profile of each brain cell type drives differential induction of secondary senescence, where some cell types can induce senescence in themselves as well as in other cell types, while other cell types are only capable of receiving secondary senescence induction, but cannot spread. Importantly, we identified both cell-type-specific and common SASP ligands and receptors, which we successfully targeted to prevent the induction of secondary senescence depending on the cell types communicating with one another. Taken together, this work gives key insights into the mechanisms of paracrine spreading of senescence between brain cell types in vitro and offers potential therapeutic targets to prevent this spreading, which may in turn help to alleviate age-related tissue decline and inflammaging.
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