Senolytics, which eliminate senescent cells from tissues, represent an emerging therapeutic strategy for various age-related diseases. Most senolytics target antiapoptotic proteins, which are overexpressed in senescent cells, limiting specificity and inducing severe side effects. To overcome these limitations, we constructed self-assembling senolytics targeting senescent cells with an intracellular oligomerization system. Intracellular aryl-dithiol-containing peptide oligomerization occurred only inside the mitochondria of senescent cells due to selective localization of the peptides by RGD-mediated cellular uptake into integrin αvβ3-overexpressed senescent cells and elevated levels of reactive oxygen species, which can be used as a chemical fuel for disulfide formation. This oligomerization results in an artificial protein-like nanoassembly with a stable α-helix secondary structure, which can disrupt the mitochondrial membrane via multivalent interactions because the mitochondrial membrane of senescent cells has weaker integrity than that of normal cells. These three specificities (integrin αvβ3, high ROS, and weak mitochondrial membrane integrity) of senescent cells work in combination; therefore, this intramitochondrial oligomerization system can selectively induce apoptosis of senescent cells without side effects on normal cells. Significant reductions in key senescence markers and amelioration of retinal degeneration were observed after elimination of the senescent retinal pigment epithelium by this peptide senolytic in an age-related macular degeneration mouse model and in aged mice, and this effect was accompanied by improved visual function. This system provides a strategy for the treatment of age-related diseases using supramolecular senolytics.
A revolutionary breakthrough in medical research has unveiled a cutting-edge technology capable of selectively removing aging cells, offering a promising new approach to treating age-related diseases. This groundbreaking development is set to redefine the future of healthcare and usher in a new era of targeted therapeutic interventions.
A research team, led by Professor Ja Hyoung Ryu from the Department of Chemistry at UNIST, in collaboration with Professor Hyewon Chung from Konkuk University, has achieved a significant breakthrough in the treatment of age-related diseases. Their cutting-edge technology offers a promising new approach by selectively removing aging cells, without harming normal healthy cells. This groundbreaking development is poised to redefine the future of healthcare and usher in a new era of targeted therapeutic interventions.
Figure 1. A schematic diagram, illustrating a groundbreaking study that specifically targets mitochondria within aging cells.
Aging cells, known as senescent cells, contribute to various inflammatory conditions and age-related ailments as humans age. To address this issue, the research team focused on developing a technology that could precisely target and eliminate aging cells, while sparing normal healthy cells.
In their study, the team designed organic molecules that selectively target receptors overexpressed in the membranes of aging cells. By leveraging the higher levels of reactive oxygen species (ROS) found in aging cells, these molecules promote the formation of disulfide bonds and create oligomers that bind together.
Through self-assembly of these oligomers, the researchers successfully created artificial proteins with a stable α-helix secondary structure. These protein-like nanoassemblies exhibited strong binding affinity to the mitochondrial membranes of aging cells, leading to membrane disruption and subsequent cell self-destruction.
Figure 2. Peptide oligomerization and self-assembly into α-helical structures.
“The selective removal of aging cells by targeting the mitochondria and inducing dysfunction has been successfully demonstrated in our experiments,” stated Professor Ryu. “This approach represents a new paradigm for treating age-related diseases.”
This innovative technology offers several advantages, including minimal toxicity concerns and a wide therapeutic window by specifically targeting organelles within cells. It opens up exciting possibilities for designing preclinical and clinical trials in the future.
Supported by the National Research Foundation of Korea (NRF) and the Ministry of Science and ICT (MSIT), this groundbreaking research has been published in the online version of the Journal of the American Chemical Society (JACS) on September 4, 2023.
Sangpil Kim, Jae-Byoung Chae, Dohyun Kim, et al., “Supramolecular Senolytics via Intracellular Oligomerization of Peptides in Response to Elevated Reactive Oxygen Species Levels in Aging Cells,” JACS (2023).