Senescent cells are damaged or stressed cells that stop dividing but don't die off as they usually should. Instead, they stay in the body, releasing harmful substances like pro-inflammatory cytokines, chemokines, and other factors. This release of damaging molecules is called the "senescence-associated secretory phenotype" (SASP). Over time, these cells accumulate and contribute to tissue damage, inflammation, and many chronic diseases, leading to "inflammaging." By removing these cells or altering their behavior, we can reduce the effects of aging and increase healthspan.
Dasatinib alone or combined with quercetin effectively targets senescent cells. However, dasatinib has adverse effects, necessitating the search for natural alternatives. Using publicly available gene expression data and computational tools, the study identified several natural compounds that mimic the hemolytic activity of dasatinib. These compounds include piperlongumine, parthenolide, phloretin, and curcumin. Each of these compounds has been previously investigated for their anti-inflammatory, anti-cancer, or anti-aging properties, but their potential for senolytic action has yet to be thoroughly explored.
Piperlongumine, found in the long pepper, emerged as the most promising dasatinib substitute. It showed significant gene expression overlap with dasatinib-treated cells, especially in apoptosis-related processes, which are critical for targeting and eliminating senescent cells. The study highlights piperlongumine’s ability to induce apoptosis in cancer and senescent cells, particularly in acute myeloid leukemia (AML) cells. Piperlongumine was found to downregulate critical genes involved in apoptosis resistance, making it a potent candidate for senolytic therapy. The compound was tested at 10 µM in various cell models, showing effectiveness in selectively targeting senescent cells without significant toxicity to normal cells.
Other compounds like parthenolide (from Tanacetum parthenium), curcumin (from Curcuma longa), and phloretin (found in apples) also showed potential but ranked lower compared to piperlongumine. These compounds, particularly parthenolide, exhibited senomorphic activity, modifying the senescence-associated secretory phenotype (SASP) without inducing apoptosis. Phloretin and curcumin were also linked to anti-apoptotic pathways but require further investigation to fully validate their senolytic potential.
Senomorphic activity refers to modifying the behavior of senescent cells without killing them. This includes reducing the harmful effects of the SASP (like inflammation) or preventing cells from becoming senescent in the first place. Essentially, senomorphics help "calm down" the senescent cells, making them less harmful. In contrast to senolytics, which kill these cells, senomorphics try to alter their behavior so they cause less damage to surrounding tissues.
The study concluded that piperlongumine, combined with quercetin, could emulate the dasatinib-quercetin combination used in current senolytic therapies. The findings suggest a pathway for developing safer, natural senotherapeutic combinations with fewer side effects than dasatinib. Additionally, the computational approach used in this study provides a cost-effective and efficient method for drug repurposing and discovering novel therapies. In vivo validation and clinical trials are needed to confirm the efficacy and safety of these natural compounds in humans.
References
Meiners, F., Hinz, B., Boeckmann, L. et al. Computational identification of natural senotherapeutic compounds that mimic dasatinib based on gene expression data. Sci Rep 14, 6286 (2024). https://doi.org/10.1038/s41598-024-55870-4
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