Clearance of Senescent Cells Improves Immune Cell Function in the Aged Brain

Immune cells resident to the brain become more activated and inflammatory with age. Researchers have found that at least some of these cells are senescent, generating inflammatory signaling. Clearing these cells via senolytic therapies, such as the well-established dasatinib and quercetin combination, reduces inflammation and markers of neurodegeneration in mice. In the study here, researchers instead use genetic means of selective senescent cell destruction in mice, and see similar improvements. There is an ongoing trial of senolytics as a means to treat Alzheimer's disease; to the degree that Alzheimer's is primarily driven by immune dysfunction and chronic inflammation in brain tissue, a view of the condition that is gaining traction, this seems a sensible test of the ability of senolytics to impact inflammatory age-related disease in humans to the same degree that it can in mice.

Cellular senescence is a plausible mediator of inflammation-related tissue dysfunction. In the aged brain, senescent cell identities and the mechanisms by which they exert adverse influence are unclear. Here we used high-dimensional molecular profiling, coupled with mechanistic experiments, to study the properties of senescent cells in the aged mouse brain. We show that senescence and inflammatory expression profiles increase with age and are brain region- and sex-specific. p16-positive myeloid cells exhibiting senescent and disease-associated activation signatures, including upregulation of chemoattractant factors, accumulate in the aged mouse brain. Senescent brain myeloid cells promote peripheral immune cell chemotaxis in vitro.

Our results suggest several scenarios by which senescent cell targeting may beneficially influence brain immune cell composition. First, p16-positive brain myeloid cells (resident microglia and infiltrating myeloid cells) may drive peripheral immune cell recruitment, and their targeting may prevent a shift to homeostatic imbalance, characterized by infiltration of activated, potentially senescent, circulating inflammatory cells. Second, other senescent cell types (e.g., p16-positive astrocytes, oligodendrocytes, and endothelial cells) may also exert proinflammatory influence and may also be cleared. Third, reducing the abundance of circulating senescent immune cells may thereby deplete the pool available for recruitment into the brain under steady-state inflammatory conditions. Fourth, systemic senescent cell elimination may reduce the abundance of senescent cells throughout the body that contributes senescence-associated secretory phenotype (SASP) factors to the circulating progeronic proteome, which is a driver of age-related brain dysfunction.

Based on the established influence of circulating senescent inflammatory cells and SASP factors as mediators of organ homeostasis, we assert that rejuvenation of the inflammatory brain cell landscape and associated improvements in cognitive function following clearance of p16-positive cells in aged mice may reflect a combination of senescent cell elimination in the brain, periphery, and circulation.



One curious finding I see in this paper is that there's a sex-specific response to p16 ablation (both in terms of gene expression and cognitive tests) via AP20187. I don't recall such a difference being observed in previous studies involving anti-p16 senolytics.

Posted by: Dylan Mah at October 4th, 2022 10:58 AM
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