You might recall that researchers recently demonstrated that vaccination against GPNMB is a senolytic strategy, reducing the harmful burden of senescent cells in aged tissues by directing the immune system to destroy these cells. Here the same team reports on their further investigation of the role of GPNMB in senescent cells. Why is GPNMB expression upregulated in senescent cells to the point of it being a good target for immune based senolytic therapies? The answer appears to be that it is protective against certain forms of stress inherent in the state of cellular senescence.
Accumulation of senescent cells in various tissues has been reported to have a pathological role in age-associated diseases. Elimination of senescent cells (senolysis) was recently reported to reversibly improve pathological aging phenotypes without increasing rates of cancer. We previously identified glycoprotein nonmetastatic melanoma protein B (GPNMB) as a seno-antigen specifically expressed by senescent human vascular endothelial cells and demonstrated that vaccination against Gpnmb eliminated Gpnmb-positive senescent cells, leading to an improvement of age-associated pathologies in mice.
The aim of this study was to elucidate whether GPNMB plays a role in senescent cells. We examined the potential role of GPNMB in senescent cells by testing the effects of GPNMB depletion and overexpression in vitro and in vivo. Depletion of GPNMB from human vascular endothelial cells shortened their replicative lifespan and increased the expression of negative cell cycle regulators. Conversely, GPNMB overexpression protected these cells against stress-induced premature senescence. Depletion of Gpnmb led to impairment of vascular function and enhanced atherogenesis in mice, whereas overexpression attenuated dietary vascular dysfunction and atherogenesis.
In conclusion, our results taken together with the above considerations demonstrated that GPNMB was upregulated by lysosomal stress associated with cellular senescence and acted as a protective factor for senescent cells, and suggest that targeting cell/tissue-specific seno-antigens like GPNMB could be a reasonable strategy for next-generation senolytic therapy with higher selectivity and fewer off-target effects.