The Problem
Early studies show that destroying senescent, or old and dysfunctional, cells can delay or even reverse diseases of aging and extend lifespan. The primary strategy for turning this into a therapy has been “senolytic” drugs that target signaling pathways that senescent cells need for survival.
The Goal
An alternative approach, targeting senescent cells based on short segments of proteins (“peptides”) on their surfaces, create a novel way to identify, target, and remove these cells.
The Status
Relevant peptides are being screened using a technology called “phage display” to discover which are relevant to senescent cells. 14 peptides have been identified that selectively target these aging cells; 4 of these have been proven to target both skin and blood vessel senescence. Two of these show significant therapeutic potential for targeting, binding to, and even killing senescent cells without negatively impacting local healthy cells or tissue.
Identification and Therapeutic Exploitation of Senescent Cell Surface Peptides
Phage display is used to identify peptides selectively present on the surfaces of senescent cells (SEN). Such senoantigens could be exploited as targets for NK cells engineered for enhanced immunosurveillance or in antibody-drug conjugates (ADCs). In preliminary screening, a phage display library identified 14 motifs present exclusively on SEN but not nonSEN endothelial cells. Follow up screening of IMR-90 fibroblasts and of endothelial cells induced to senescence by alternative means identified four conserved SEN-selective peptides.
Peptide 6 is the most highly selective of the 4 conserved peptides, binding SEN and not nonSEN regardless of cell type of origin or induction mode, and it is being developed for use in SEN localization and quantitation in mouse tissues. Peptide 18 has emerged as a directly senolytic peptide. SEN culture viability declined when exposed to this peptide during testing. Following independent replication and measurement of cell survival using crystal violet staining, comparative experiments using Peptide 2 as a negative control demonstrated that Peptide 18 selectively destroys 42% of SEN while exhibiting no toxicity toward either senescent or non-senescent cells; Peptide 2 had no effect on the viability of either cell type.
These effects were further observed in real time using the xCELLigence RTCA MP, demonstrating significant cytotoxicity in SEN incubated with Peptide 18 within 4 hours. Follow up experiments demonstrated that Peptide 18 induces senolysis via apoptosis rather than necrosis.
Team Members
Please visit the Work With Us page to learn about available positions.
Dr. Amit Sharma
Principal Investigator
Dr. Amit Sharma was awarded a Master’s degree in Biomedical Sciences from Delhi University, India. He received his PhD in 2009 in Biotechnology from University of Pune for his work demonstrating microRNA regulation of cytokines involved in allergic inflammation in mice model. Dr. Sharma’s postdoctoral research at the Buck Institute, Novato California involved investigating novel molecular regulatory pathways involved in genotoxic stress and cellular senescence in invertebrate and mammalian models.
Dr. Sharma is the SENS Research Foundation Group Lead in the Senescence Immunology Research Group. His research focus involves studying how aging and senescence affects the immune system and his research group will also investigate strategies to harness the immune system in mitigating deleterious effects of senescent cells with translational focus.
Funding
Annual Budget
100,000 USD
