Fight Aging!

Senolytic drugs selectively destroy senescent cells. First generation senolytic drugs generally target apoptosis-resistance mechanisms and have off-target effects, though these appear quite acceptable in the case of dasatinib and quercetin, given the potential benefits. Nonetheless, researchers are expending a great deal of effort to search for ways to produce far more selective targeting of senescent cells. One example is the category of prodrugs that are only transformed into their cytotoxic form via the activity of β-galactosidase, upregulated in senescent cells. Another type of prodrug employs iron metabolism peculiar to senescent cells. Today's example is more complex than either of those, and quite interesting.

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 (ROS), 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 integity 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.

Link: https://doi.org/10.1021/jacs.3c06898