Cell-Surface LAMP1 is a Senescence Marker in Aging and Idiopathic Pulmonary Fibrosis

The accumulation of senescent cells (SEN) with aging produces a chronic inflammatory state that accelerates age-related diseases. Eliminating SEN has been shown to delay, prevent, and in some cases reverse aging in animal disease models and extend lifespan. There is thus an unmet clinical need to identify and target SEN while sparing healthy cells. Here, we show that Lysosomal-Associated Membrane Protein 1 (LAMP1) is a membrane-specific biomarker of cellular senescence. We have validated selective LAMP1 upregulation in SEN in human and mouse cells. Lamp1+ cells express high levels of prototypical senescence markers p16, p21, Glb1, and have low Lmnb1 expression as compared to Lamp1- cells. The percentage of Lamp1+ cells is increased with age and in mice with fibrotic lungs due to bleomycin instillation. The RNA-Seq. analysis of the Lamp1-enriched populations in sham and BLM mice lung tissue revealed enrichment of several senescence-related genes in both groups when compared to the SenMayo gene set derived from transcriptomic profiling of senescence markers in Mayo Clinic research datasets. Finally, we use a dual antibody-drug conjugate (ADC) strategy to eliminate senescent cells in cell culture assay. Lungs from Sham- and Bleomycin-treated mice were harvested. Cells were sorted to enrich or depleted cells expressing surface Lamp1. There are 6 conditions in total. For each Sham and Bleomycin, there are unsorted single cells (whole lung population, all), enriched cells (Lamp1-positive), depleted cells (Lamp1-negative).