Scientists have identified a senescence-associated surface protein that can be targeted using antibodies and published their work as a pre-print [1]. This discovery might help distinguish between beneficial and harmful senescent cells and could speed up the development of senolytic therapies. This work was done by the Lifespan Research Institute, which was formed last year by the merger of SENS Research Foundation and Lifespan.io.
Shedding light on senescence
Most geroscientists agree on two things: cellular senescence is an important driver of aging, and senescent cells are notoriously difficult to study and target because of their heterogeneity. Senescent cells are often described as damaged or exhausted cells that stop dividing but remain alive, releasing pro-inflammatory factors that can induce senescence in neighboring cells. While cellular senescence plays a beneficial role in some processes related to development, wound healing, and anti-cancer surveillance, the overall senescence burden grows with age, tipping the scale towards harm.
The answer is on the surface
Senescent cells are known to exhibit increased lysosomal activity [2]. Lysosomes are bubble-like organelles that envelop intracellular junk and transport it outside the cell by fusing with the cell’s outer membrane in a process called lysosomal exocytosis. The underlying causes of excessive intracellular waste in senescent cells are not entirely clear, but this process may contribute to senescence-related inflammation.
Working with a publicly available database of membrane proteins, the researchers zeroed in on the protein LAMP1, which is abundant in lysosomal membranes. In healthy cells, “LAMP1 is only briefly found at the cell surface due to the fusion of lysosomes with the plasma membrane, and thus, mostly undetectable,” the paper says. However, LAMP1 is known to linger in membranes of some cancer cells, probably due to their increased lysosomal exocytosis.
The dataset revealed a strong correlation between LAMP1 expression and other known senescence-related genes, such as p21 and p16, but the researchers had to confirm this in actual cells. After inducing senescence in human fetal lung fibroblasts in three different ways, they observed a significant increase in the proportion of LAMP1-positive cells. While only about 1% of non-senescent cells expressed LAMP1 on their membranes, 20% to 60% of senescent cells expressed it.
The researchers then isolated both LAMP1-positive and LAMP1-negative cell populations from the liver and lungs of middle-aged mice and found that the former expressed additional senescence markers.
Telling good from evil
As their in vivo model, the researchers chose mice treated with bleomycin, which induces a condition similar to idiopathic pulmonary fibrosis (IPF) – a deadly and currently uncurable age-related lung disease. IPF has long been suspected to be driven by increased cellular senescence.
Experiments detected a 1.5- to 3-fold increase in the number of LAMP1-positive cells after the bleomycin treatment relative to controls. Interestingly, in healthy mice, LAMP1 was expressed mostly by a fraction of one cell type: endothelial cells. In contrast, bleomycin-treated mice showed LAMP1 expression across multiple cell types.
This difference might be important for distinguishing between beneficial and harmful senescent cells. “Another interesting observation is that in healthy mice, most senescent cells in the lung were endothelial cells,” said Dr. Amit Sharma, who led the study. “In contrast, in bleomycin-treated mice that showed increased inflammation, the majority of senescent cells were of myeloid origin. It is possible that another layer of complexity in the heterogeneity of senescence is the type of cells contributing to pathology vs tissue repair.”
He further explained, “There has been a discussion of good vs bad senescent cells, so is it possible that these myeloid senescent cells are the bad ones? There is some evidence by others that this might be true, at least in liver fibrosis [3], where eliminating p16-expressing fibroblasts slows down tissue repair, while p16-expressing macrophages can be beneficial. Of course, this must be further tested. If LAMP1 is reliably seen as a senescence biomarker, we can develop drugs specifically targeting bad senescent cells, which would be safer.”
Targeting LAMP1
Lastly, the researchers made the first steps towards confirming LAMP1 as a possible target for intervention. Working on cells in culture, they used an antibody-drug conjugate (ADC), a construct consisting of an antibody that targets a specific surface protein, in this case LAMP1, and a drug that kills the targeted cell (technically, the ADC targeted another antibody, which targeted LAMP1). The treatment caused substantial cytotoxicity in senescent cells and virtually none in non-senescent cells.
According to Sharma, identifying LAMP1 as a surface biomarker of senescence is significant. Unlike cytosolic markers that remain inside the cell, surface biomarkers might allow easier detection, study, and targeting of senescent cells.
“Senescent cell biomarker discovery is the holy grail of senescence research,” Sharma said. “This will be useful for understanding how senescent cells contribute to pathology and validating the efficacy of interventions. If what we found in the IPF mouse model and in middle-aged mice is true for other senescence models, a surface marker offers a huge possibility for diagnostic tool development.”
Literature
[1] Cell-Surface LAMP1 is a Senescence Marker in Aging and Idiopathic Pulmonary Fibrosis (2025). Gabriel Meca-Laguna, Michael Qiu, Anna Barkovskaya, Apoorva Shankar, Michael Rae, Amit Sharma. BioRxiv
[2] Rovira, M., Sereda, R., Pladevall‐Morera, D., Ramponi, V., Marin, I., Maus, M., … & Serrano, M. (2022). The lysosomal proteome of senescent cells contributes to the senescence secretome. Aging Cell, 21(10), e13707.
[3] Zhao, H., Liu, Z., Chen, H., Han, M., Zhang, M., Liu, K., … & Zhou, B. (2024). Identifying specific functional roles for senescence across cell types. Cell, 187(25), 7314-7334.
View the article at lifespan.io
