Cell-Surface LAMP1 is a Senescence Marker in Aging and Idiopathic Pulmonary Fibrosis
Gabriel Meca-Laguna1, Michael Qiu1,2, Yafei Hou1
1Lifespan Research Institute, Mountain View, California, USA.
Abstract:
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 the 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 (BLM) instillation. The RNA-Sequencing 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 SEN in cell culture assay.
Insights
Cellular senescence (SEN) drives aging and age-related diseases. Researchers identified Lysosomal-Associated Membrane Protein 1 (LAMP1) as a novel biomarker for targeting senescent cells, offering a potential therapeutic strategy.
Area of Science:
- Cellular Biology
- Aging Research
- Immunology
Background:
- Cellular senescence (SEN) accumulation with aging causes chronic inflammation, accelerating age-related diseases.
- Eliminating senescent cells shows potential in delaying, preventing, and reversing aging phenotypes in animal models.
- There is a critical need for methods to selectively identify and target senescent cells while preserving healthy cells.
Purpose of the Study:
- To identify a specific biomarker for cellular senescence.
- To validate the identified biomarker in human and mouse cells.
- To explore therapeutic strategies for eliminating senescent cells.
Main Methods:
- Validated Lysosomal-Associated Membrane Protein 1 (LAMP1) as a membrane-specific biomarker for cellular senescence.
- Confirmed LAMP1 upregulation in senescent cells (SEN) across human and mouse cell lines.
- Utilized RNA-sequencing to analyze gene expression in LAMP1-enriched populations from mouse lung tissue.
- Employed a dual antibody-drug conjugate (ADC) strategy in cell culture assays to eliminate SEN.
Main Results:
- LAMP1 is selectively upregulated in SEN, correlating with established senescence markers (p16, p21, Glb1) and inversely with Lmnb1.
- The proportion of LAMP1-positive cells increases with age and in bleomycin-induced lung fibrosis models.
- RNA-sequencing revealed enrichment of senescence-related genes in LAMP1-positive populations.
- Demonstrated the efficacy of an ADC strategy in eliminating SEN in vitro.
Conclusions:
- LAMP1 serves as a reliable and specific biomarker for cellular senescence.
- Targeting LAMP1 presents a promising strategy for the selective elimination of senescent cells.
- This approach holds potential for therapeutic interventions in age-related diseases.
