Taking sniper aim at ‘pro-aging’ senescent cells by studying their surface proteome and then marking their skin with a big bullseye if four unique cell surface proteins are present looks like a promising move IMHO. Crossing fingers here it takes us all a step closer to an antisenescence vaccine sooner than later.
Abstract
The accumulation of senescent cells is thought to play a crucial role in aging-associated physiological decline and the pathogenesis of various age-related pathologies. Targeting senescence-associated cell surface molecules through immunotherapy emerges as a promising avenue for the selective removal of these cells. Despite its potential, a thorough characterization of senescence-specific surface proteins remains to be achieved. Our study addresses this gap by conducting an extensive analysis of the cell surface proteome, or “surfaceome”, in senescent cells, spanning various senescence induction regimes and encompassing both murine and human cell types. Utilizing quantitative mass spectrometry, we investigated enriched cell surface proteins across eight distinct models of senescence. Our results uncover significant changes in surfaceome expression profiles during senescence, highlighting extensive modifications in cell mechanics and extracellular matrix remodeling. Our research also reveals substantive heterogeneity of senescence, predominantly influenced by cell type and senescence inducer. A key discovery of our study is the identification of four unique cell surface proteins with extracellular epitopes. These proteins are expressed in senescent cells, absent or present at low levels in their proliferating counterparts, and notably upregulated in tissues from aged mice and an Alzheimer’s disease mouse model. These proteins stand out as promising candidates for senotherapeutic targeting, offering potential pathways for the detection and strategic targeting of senescent cell populations in aging and age-related diseases.
…/… [CS: Cellular Senescence]
4 DISCUSSION
Cell surface proteins act as vital molecular mediators, facilitating crucial cellular functions such as cell–cell communication and metabolite transport. Notably, 66% of drugs approved in the DrugBank database target cell surface proteins (Bausch-Fluck et al., 2018). The surfaceome is highly context-dependent and varies extensively across distinct pathological conditions, reflecting its diverse and dynamic functions (Bausch-Fluck et al., 2018). Senescent cells differ from proliferating cells and display distinct metabolic, as well as protein expression patterns (Hernandez-Segura et al., 2018). Critical to understanding the mechanisms that shape the senescent phenotype is the CS surfaceome which governs interactions with the extracellular microenvironment.
Our findings indicate that the surfaceome is strongly influenced by CS, revealed by the sizeable expression differences between senescent versus non-senescent states. The extensive CS-associated changes in surfaceome expression profiles are in line with alterations in a number of cellular functionalities. Senescent cells, for instance, have altered cell adhesion capabilities, which are closely linked to cytoskeletal reorganization, morphological changes and changes in cell migration rates.
…/…
Ideal senotherapy targets should be highly and specifically expressed on senescent cells while sparing normal vital tissues. Among our potential candidates, four cell-surface proteins with predicted extracellular epitopes exhibiting relatively low or absent expression across diverse vital tissues emerged.
…/… [SASP: Senescence-Associated Secretory Phenotype] [ECM: Extracellular Matrix]
In summary, our comprehensive investigation of the CS surfaceome highlights CS surface protein changes consistent with pronounced alterations in cell mechanics and compositional ECM remodeling beyond the canonical SASP. The in-depth characterization of CS surfaceome heterogeneity, shaped by cell type and senescence inducer, lays the foundation for the development of a more rational targeted immune-based senotherapy. Future endeavors could leverage advanced technologies such as imaging flow cytometry and single-cell proteomics to further expand our understanding of senescence surface signatures in vivo. The potential utility of the CS surface markers we identified, which exhibit both shared and tissue-specific upregulation patterns, in targeting senescent cells in aging and age-related diseases in vivo, will be the focus of forthcoming research.
https://onlinelibrary.wiley.com/doi/10.1111/acel.14312
