LAMP1 Emerges as a Trackable Surface Marker for Senescent Cells in Aging and Lung Disease
Researchers identify LAMP1 on the cell surface as a reliable senescence biomarker, rising with age and in fibrotic lungs, enabling targeted senolytic therapy.
Summary
Scientists at the Lifespan Research Institute have identified LAMP1 (CD107a), a lysosomal membrane protein, as a stable cell-surface biomarker of senescent cells. Normally confined to lysosomes, LAMP1 appears prominently on the outer membrane of senescent cells in culture and in aging mouse tissues. Its presence increases with age across multiple tissues and spikes in bleomycin-induced fibrotic lungs — a model of idiopathic pulmonary fibrosis. RNA-sequencing confirmed that LAMP1-positive cells are enriched for established senescence gene signatures. The team also demonstrated that a dual antibody-drug conjugate strategy targeting surface LAMP1 can selectively kill senescent cells, opening a potential therapeutic avenue for age-related diseases.
Detailed Summary
Cellular senescence — the irreversible arrest of damaged cells — accumulates with age and drives chronic inflammation, accelerating conditions such as idiopathic pulmonary fibrosis (IPF), cardiovascular disease, and neurodegeneration. A major bottleneck in developing senolytic therapies is the absence of a robust, universally applicable biomarker that can identify senescent cells in living tissue without requiring cell permeabilization or fixation.
This study identifies Lysosomal-Associated Membrane Protein 1 (LAMP1/CD107a) as a durable cell-surface marker of senescence. The authors first conducted computational analyses of publicly available proteomic screens and single-cell transcriptomic data, finding that lysosome-related proteins — particularly LAMP1 — are consistently enriched on the surface of senescent cells across multiple cell types, senescence-inducing stimuli, and species. LAMP1 expression correlated strongly with canonical senescence markers p21 (R=0.94), p16, and BAX in healthy human tissue datasets.
In culture, human fetal lung fibroblasts (IMR-90) made senescent by doxorubicin showed striking LAMP1 surface expression: while only ~1% of non-senescent cells displayed surface LAMP1, 20–60% of senescent cells were LAMP1-positive by flow cytometry, with a five-fold increase in mean fluorescence intensity. This surface expression built progressively over days 1–7 post-insult and was reproduced with etoposide-induced senescence and in replicatively senescent cells at high passage numbers. LAMP1-positive sorted cells expressed significantly higher levels of p16, p21, SA-β-galactosidase activity, and lower lamin B1 — key canonical senescence hallmarks — compared to LAMP1-negative cells.
In vivo, the percentage of Lamp1-positive cells increased with natural aging in multiple mouse tissues. In a bleomycin (BLM) lung fibrosis model mimicking IPF, Lamp1-positive cells were significantly elevated in fibrotic lungs compared to sham controls. Critically, RNA-sequencing of Lamp1-sorted lung cell populations confirmed strong enrichment of the SenMayo senescence gene signature in Lamp1-positive versus Lamp1-negative fractions in both sham and BLM conditions, providing transcriptomic validation. Finally, the team demonstrated proof-of-concept for a dual antibody-drug conjugate (ADC) strategy using LAMP1-targeting antibodies to selectively eliminate senescent cells in culture, with significant reduction in the senescent cell population.
These findings establish cell-surface LAMP1 as a promising, cell-type-agnostic, stimulus-agnostic biomarker of senescence that can be detected on living, intact cells — a key advantage over intracellular markers. While most prior surface senescence markers (uPAR, DPP4, B2M) have been identified in specific contexts, LAMP1's upregulation across diverse cell types and induction modalities suggests broader utility. The authors propose LAMP1 as both a diagnostic tool for quantifying senescent burden in aging and disease and as a therapeutic target for next-generation senolytic ADC strategies.
Key Findings
- Cell-surface LAMP1 is expressed on 20–60% of senescent fibroblasts vs. ~1% of non-senescent controls by flow cytometry.
- LAMP1 expression correlates with senescence markers p21 (R=0.94), p16, and BAX across healthy human tissue datasets.
- Lamp1-positive cells increase with natural aging in multiple mouse tissues and spike in bleomycin-induced fibrotic lungs.
- RNA-sequencing confirms Lamp1-positive lung cells are enriched for the SenMayo senescence gene signature in vivo.
- A LAMP1-targeting antibody-drug conjugate selectively eliminates senescent cells in proof-of-concept culture experiments.
Methodology
The study combined computational analysis of public proteomic and transcriptomic datasets with in vitro experiments using doxorubicin- and etoposide-induced senescence in IMR-90 fibroblasts, validated by flow cytometry, immunofluorescence, and FACS sorting. In vivo validation used natural aging mouse cohorts and a bleomycin lung fibrosis mouse model, with LAMP1-sorted populations analyzed by bulk RNA-sequencing and compared to the SenMayo gene signature.
Study Limitations
The in vivo ADC senolytic experiments were conducted only in cell culture, leaving efficacy and safety in animal models undemonstrated. LAMP1 surface expression in immune cells during activation (cytotoxic degranulation) may complicate specificity in immunological contexts. The study does not yet establish whether serum or circulating LAMP1 levels reflect tissue senescent burden, limiting non-invasive clinical translation.
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