2023-10-10 17:12:03
Senolytics, which eliminate aging cells from tissues, represent a promising therapeutic strategy to treat many age-related diseases. However, they have limitations due to their reduced ability to distinguish target cells from healthy cells — which can lead to significant side effects. A new range of supramolecular senolytics recently developed could be a game-changer, by selectively destroying senescent cells without affecting healthy cells.
Aging, or cellular senescence, is a process induced by cell cycle arrest, causing major biomolecular changes. These modifications include alterations at the level of the epigenome, transcriptome, proteome and secretome, and cause significant metabolic damage as well as an alteration of the apoptotic cycle (programmed cell death). These cells accumulate as we age and contribute to the pathogenicity of many age-related conditions.
The proliferation of senescent cells is linked to a specific secretome called “Senescence-Associated Secretory Phenotype” (SASP). This factor stimulates the release of inflammatory cytokines, chemokines, extracellular matrix degrading enzymes, and many other bioactive compounds leading to tissue damage. Senescence markers also impede the function of stem and progenitor cells, converting them into senescent cells that spread locally and systemically.
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Much research in the biology of aging suggests that reducing the burden of senescent cells could be a promising therapeutic strategy to treat a wide range of diseases. Of the experiences previously demonstrated that transplantation of aging cells into young mice shortened their lifespan and accelerated the onset of age-related disease phenotypes. These results led to the emergence of a new category of active ingredients: senolytics. As their name suggests, these molecules aim to selectively eliminate aging cells and thus reduce the negative impacts of their accumulation in tissues.
However, previously developed senolytics have major limitations. Since most are involved in anti-apoptotic proteins, their ability to specifically target senescent cells is low. Among other things, they do not distinguish between cells to be eliminated and healthy cells, which can lead to serious side effects. To address this problem, researchers at Ulsan National Institute of Science and Technology (UNIST) and Konkuk University (both in South Korea) developed novel supramolecular senolytics capable of targeting only senescent cells without affecting healthy cells.
A strategy targeting mitochondria
As part of the new study, South Korean researchers developed senolytics that selectively target receptors overexpressed on the mitochondrial membranes of senescent cells. In the presence of high levels of reactive oxygen species (ROS), inherent to oxidative stress and aging, therapeutic molecules stimulate the formation of disulfide bonds between the oligomers present. Then, the latter self-assemble so as to form stable alpha helix-shaped protein structures, having a strong affinity with the mitochondrial membranes of aging cells. Binding with their target receptors leads to membrane rupture and thus cellular self-destruction.
Illustration summarizing how new senolytics work. © Sangpil Kim et al.
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This strategy has a major advantage in selectivity because oligomerization occurs only inside senescent cells. On the other hand, membrane destruction only affects the target cells, because they already have low integrity of their mitochondrial membrane, compared to healthy cells.
To test their senolytics, the researchers selected aged mice with age-related macular degeneration (AMD). “ Selective elimination of aging cells by targeting mitochondria and causing dysfunction was successfully demonstrated in our experiments », explains in a communiqué Ja Hyoung Ryu, from UNIST’s Department of Chemistry, who led the study, published in the Journal of the American Chemical Society. Significant reductions in key markers of senescence and aging retinal pigment epithelial cells were observed. These effects were accompanied by an improvement in visual function.
These results suggest that newly developed senolytics not only reduce the toxicity problems associated with this type of therapy, but also offer a broad therapeutic window by targeting cellular organelles. “ This approach represents a new paradigm for treating age-related diseases », concludes Ryu. Ultimately, this type of therapy could help treat many conditions, ranging from neurodegeneration to osteoporosis, including AMD and skin aging.
Source : Journal of the American Chemical Society
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