Using a Surface Biomarker to Target Senescent Cells

This biomarker may be useful in distinguishing harmful from helpful cells.

By Arkadi

March 14, 2025

Scientists have identified a surface biomarker that could help distinguish between beneficial and harmful senescent cells, potentially accelerating the development of senolytic therapies. This work was conducted by the Lifespan Research Institute, formed last year through the merger of the SENS Research Foundation and Lifespan.io.

Shedding Light on Senescence

Most geroscientists agree on two points: cellular senescence is a critical driver of aging, and senescent cells are notoriously difficult to study due to their heterogeneity. Senescent cells are often described as damaged or exhausted cells that cease to divide yet remain viable, releasing pro-inflammatory factors that can induce senescence in neighboring cells. While cellular senescence serves a beneficial role in processes like development, wound healing, and anti-cancer surveillance, the overall senescence burden increases with age, leading to detrimental outcomes.

The Answer is on the Surface

Senescent cells are characterized by heightened lysosomal activity ^[2]. Lysosomes, which are organelles that encapsulate and transport cellular waste, play a crucial role in managing cellular health. The underlying reasons for the accumulation of intracellular waste within senescent cells remain elucidatory; however, this mechanism may contribute to senescence-associated inflammation.

Utilizing a publicly available database of membrane proteins, researchers focused on the protein LAMP1, found abundantly in lysosomal membranes. In normal cells, LAMP1 is minimally present at the cell surface due to its transient nature involved in lysosomal exocytosis. Contrarily, it persists in some cancer cells, likely due to their heightened rates of lysosomal exocytosis.

The researchers discovered a robust correlation between LAMP1 expression and various senescence-related genes, including p21 and p16. To verify these findings, they induced senescence in human fetal lung fibroblasts using three distinct methodologies, revealing a significant increase in LAMP1-positive cells: only about 1% of non-senescent cells expressed LAMP1, while 20% to 60% of senescent cells did.

Telling Good from Evil

Researchers adopted an in vivo model, using mice treated with bleomycin, which induces a condition akin to idiopathic pulmonary fibrosis (IPF), a fatal age-related lung disease suspected of being driven by increased cellular senescence.

Results from the experiment indicated a 1.5- to 3-fold increase in LAMP1-positive cells post-bleomycin treatment compared to controls. In healthy mice, LAMP1 expression was predominantly confined to one cell type: endothelial cells. In contrast, bleomycin-treated mice exhibited LAMP1 expression across various cell types.

This distinction may be pivotal for differentiating between beneficial and harmful senescent cells. “Another interesting observation is that in healthy mice, the majority of senescent cells in the lung were endothelial cells,” stated Dr. Amit Sharma, the study's lead researcher. “In contrast, in bleomycin-treated mice with heightened inflammation, most senescent cells were derived from myeloid origins.” This suggests that the type of senescent cells may influence the pathological or reparative functions they serve.

Dr. Sharma suggested the potential classification of senescent cells into 'good' and 'bad' categories – a hypothesis supported by findings in liver fibrosis ^[3], where eliminations of p16-expressing fibroblasts slow tissue repair, in contrast to the beneficial roles of p16-expressing macrophages.

Targeting LAMP1

The researchers took initial steps to confirm LAMP1 as a target for therapeutic intervention. They employed an antibody-drug conjugate (ADC) system, consisting of an antibody directed toward LAMP1 and a cytotoxic drug. This treatment yielded substantial cytotoxic effects on senescent cells while sparing non-senescent cells.

Sharma emphasized the significance of identifying LAMP1 as a surface biomarker of senescence: “Senescent cell biomarker discovery is the holy grail of senescence research. This will enable us to understand how senescent cells contribute to pathology and validate the efficacy of interventions.” If this discovery applies in broader senescence models, it could pave the way for new diagnostic tools.

Literature Cited

• [1] Meca-Laguna, G., et al. (2025). Cell-Surface LAMP1 is a Senescence Marker in Aging and Idiopathic Pulmonary Fibrosis. BioRxiv.
• [2] Rovira, M., et al. (2022). The lysosomal proteome of senescent cells contributes to the senescence secretome. Aging Cell, 21(10), e13707.
• [3] Zhao, H., et al. (2024). Identifying specific functional roles for senescence across cell types. Cell, 187(25), 7314-7334.

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