Senolytics: Dasatinib and Quercetin

The health and lifespan of mice have been demonstrated to improve by the removal of senescent cells using a transgenic suicide gene (Darren et al., 2011) and later experiments showed the same could be achieved using small molecules. Senolytics are a relatively new class of drugs that focuses on the removal of senescent cells. These senescent cells comprise a small number of total cells in the body but they secrete pro-inflammatory cytokines, chemokines, and extracellular matrix proteases, which together form the senescence-associated secretory phenotype or SASP. The resulting SASP is thought to significantly contribute to aging (Freund, Campisi, et al, 2010) and cancer (Coppé, Campisi, et al, 2010) and thus Senolytics and removal of SASP is a potential strategy for promoting health and longevity.

 

It was discovered through transcript analysis that senescent cells have increased expression of pro-survival genes, consistent with their resistance to apoptosis (Zuh et al., 2015). Drugs targeting these pro-survival factors selectively killed senescent cells. Two such drugs were Dasatinib and quercetin which were both able to remove senescent cells but were better in differing tissue types. However it was discovered that a combination of the two drugs formed a synergy that was significantly more effective at removing some senescent cell types (Zuh et al., 2015).

 

In other studies whilst only removing thirty percent of senescent cells there were improvements to age related decline. These results suggest the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of aging and promoting healthy longevity (Tchkonia et al., 2013; Kirkland et al., 2014; Kirkland and Tchkonia, 2015).

 

However to date the combination of Dasatinib and Quercetin has yet to be tested in relation to its potential to increase healthy lifespan. Current Senolytic studies have focused only on health improvements rather than the long term effects (either bad or good) of this type of approach. The MMTP aims to address this missing and vitally important question, can Senolytics promote healthy longevity?

 

The removal of senescent cells appears to convey a number of health benefits and we are keen to explore its potential in relation to lifespan. The SENS research foundation along with the Campisi lab have been particular proponents of senolytics as a potential toolkit to combat age related decline. SENS research foundation has funded exploration of senolytics and an explanation of their rationale is here.

 

The following data relating to Quercetin taken alone from geroprotectors shows some benefits to lifespan in studies conducted so far though the synergy of both compounds is yet to be explored fully, we intend to redress this and obtain senolytic lifespan data.

 

NameOrganism_nameMean LS (%)Median LS (%)Max LS (%)Reference
QuercetinCaenorhabiditis elegans 21 19043800
Quercetin DihydrateDrosophila melanogaster23  22363408
Quercetin-3-O-GlucosideCaenorhabiditis elegans23  23856528
   
http://www.geroprotectors.org/