Arguably the primary reason why the number of senescent cells increases with age throughout the body is the growing failure of the immune system to clear these errant cells. The reasons for that failure are not well understood in detail, though some inroads have been made into that area of research. Both the innate and adaptive immune system are involved in clearance of senescent cells, so in principle there should be a plethora of mechanisms that could be targeted in order to create immunotherapies that increase the pace at which the immune system clears senescent cells. Both SIWA Therapeutics and Deciduous Therapeutics are working on approaches to this goal.
Today's research materials discuss a different way forward. If senescent cells have surface features that are distinctive enough, not shared to a large degree with other cells, then it should be possible to immunize against one of those features, and have the adaptive immune system vigorously attack senescent cells for an extended period of time, perhaps years or more. Such surface features should exist, because the immune system does in fact recognize and clear senescent cells. The work of SIWA Therapeutics is based on use of a specific set of surface features, but it seems likely that there will be variance in such features from tissue to tissue. The paper I point out today focuses on one tissue only, the vascular endothelium, as the researchers involved are interested in the role of cellular senescence in the progression of atherosclerosis. Their findings may or may not generalize to any other tissues.
Elimination of senescent cells (senolysis) was recently reported to improve normal and pathological changes associated with aging in mice. However, most senolytic agents inhibit antiapoptotic pathways, raising the possibility of off-target effects in normal tissues. Identification of alternative senolytic approaches is therefore warranted. Here we identify glycoprotein nonmetastatic melanoma protein B (GPNMB) as a molecular target for senolytic therapy. Analysis of transcriptome data from senescent vascular endothelial cells revealed that GPNMB was a molecule with a transmembrane domain that was enriched in senescent cells (seno-antigen). GPNMB expression was upregulated in vascular endothelial cells and/or leukocytes of patients and mice with atherosclerosis.
Genetic ablation of Gpnmb-positive cells attenuated senescence in adipose tissue and improved systemic metabolic abnormalities in mice fed a high-fat diet, and reduced atherosclerotic burden in apolipoprotein E knockout mice on a high-fat diet. We then immunized mice against Gpnmb and found a reduction in Gpnmb-positive cells. Senolytic vaccination also improved normal and pathological phenotypes associated with aging, and extended the male lifespan of progeroid mice. Our results suggest that vaccination targeting seno-antigens could be a potential strategy for new senolytic therapies.