In Search of Natural Senolytics to Substitute for Dasatinib
Dasatinib and quercetin used in combination clears a fraction of lingering senescent cells in aging mice, producing a sizable degree of rejuvenation, and reversal of aspects of many different age-related conditions. In humans, clinical trials are underway at a sedate pace. Dasatinib is a chemotherapeutic small molecule, while quercetin is a plant extract flavonol. Here, researchers discuss their search for plant extract alternatives that mimic the effects of dasatinib, in the hopes of producing a less regulated alternative to the use of a small molecule drug, thereby lowering the barrier to entry somewhat. Size of effect is important, however, and it is yet to be demonstrated that any of their proposed alternatives can replicate the degree to which dasatinib impacts senescent cells.
The major risk factor for chronic disease is chronological age, and age-related chronic diseases account for the majority of deaths worldwide. Targeting senescent cells that accumulate in disease-related tissues presents a strategy to reduce disease burden and to increase healthspan. The senolytic combination of the tyrosine-kinase inhibitor dasatinib and the flavonol quercetin is frequently used in clinical trials aiming to eliminate senescent cells.
Here, our goal was to computationally identify natural senotherapeutic repurposing candidates that may substitute dasatinib based on their similarity in gene expression effects. The natural senolytic piperlongumine (a compound found in long pepper), and the natural senomorphics parthenolide, phloretin, and curcumin (found in various edible plants) were identified as potential substitutes of dasatinib. The gene expression changes underlying the repositioning highlight apoptosis-related genes and pathways. The four compounds, and in particular the top-runner piperlongumine, may be combined with quercetin to obtain natural formulas emulating the dasatinib + quercetin formula.