Senescent cells accumulate with age throughout the body, either in response to forms of damage and stress or on reaching the Hayflick limit on replication. A senescent cell ceases to replicate, grows in size, and secretes a potent mix of pro-growth, pro-inflammatory signals. In youth, the immune system efficiently clears senescent cells, but with age this clearance falters. Like most of the progression of degenerative aging, the accumulation of senescent cells with age is nonlinear. This is in part because the decline of the immune system accelerates in later life, but it is also the case that the signaling generated by senescent cells can induce nearby cells to also become senescent. Thus senescent cells emerge at an accelerating pace as their numbers grow.
In today’s open access paper, researchers report on an investigation of the specific details as to how senescence spreads between cells in the aging brain: which signals are involved, and which cells propagate senescence most aggressively. As one might expect, as nothing is simple in biology, there is quite a variety between cell types in the fine details of the inflammatory signaling generated and in the response to those signals. This characterization of senescent cell signaling is a necessary groundwork for later efforts to take present day approaches to interfering in unwanted inflammation and adapt them to target the harmful effects of senescent cells. While most drug development in the field of cellular senescence is presently aimed at selectively destroying senescent cells, there is growing interest in instead finding ways to suppress senescent cell signaling or its consequences while leaving the cells themselves intact.
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 select secondary senescence hallmarks 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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