Cell surface proteins distinctive to senescent cells can be used as a foundation for immunotherapies that target these cells for destruction. Partial clearance of the age-related burden of lingering senescent cells via small molecule drugs that provoke apoptosis has been shown to produce rejuvenation in aged mice and promising initial results in small human trials, but researchers continue to search for approaches that can remove a greater fraction of senescent cells. Here, find an example of work on surface features of senescent cells, in which a cell surface marker is identified and exploited to construct a proof of principle immunotherapy.
One of the most well-documented hallmarks of senescent cells is their increased lysosomal content and activity. This hallmark feeds into multiple other features of senescence, such as changes in morphology, the senescence-associated secretory phenotype (SASP), and metabolic alterations. Indeed, early efforts quantifying lysosomal activity resulted in the discovery of senescence-associated β-galactosidase (SA-β-Gal), one of the most widely used biomarkers of senescence.
Lysosomal Associated Membrane Protein 1 (LAMP1, also known as CD107a) is a master orchestrator of the structural integrity of lysosomes. LAMP1, as a type I transmembrane glycoprotein, is mostly localized in late endosomes and lysosomes. In immune cells, CD107a is also a cell-surface marker of immune activation and cytotoxic degranulation; however, its expression on the plasma membrane is transient and the protein is internalized rapidly. LAMP1 is only briefly found at the cell surface of healthy cells due to the fusion of lysosomes with the plasma membrane, and is thus mostly undetectable.
The ability to identify and characterize senescent cells is crucial for understanding their role in aging and developing targeted interventions. Here, we describe LAMP1 as a cell surface-specific marker of senescence. LAMP1's presence on the cellular membrane is highly increased in human and mouse senescent cells. In mouse tissue, cells expressing LAMP1 on their surface showed features of senescence. Additionally, senescence induction in the lungs of mice using bleomycin caused an increase in LAMP1+ cells. Finally, senescent cells are eliminated using a LAMP1-targeting antibody. These findings describe a biomarker that can be leveraged to further understand and target senescent cells.
Link: https://doi.org/10.1101/2025.03.04.640878
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