An Example of Senolytics Impoving Metabolic Function in Old Mice

The first senolytic therapy to be tested in mice and humans was the combination of dasatinib and quercetin. This continues to be tested in human trials by the Mayo Clinic, and has been shown to reduce the burden of senescent cells in humans to much the same degree as it does in mice. It remains to be seen as to whether any of the many forms of senolytic treatment under development are very much better at clearing senescent cells from aged tissues than dasatinib and quercetin. Either way, it is likely that the use of multiple different senolytics will be better than one alone, due to tissue by tissue differences in biodistribution and effectiveness.

Aging results in an elevated burden of senescent cells, senescence-associated secretory phenotype (SASP), and tissue infiltration of immune cells contributing to chronic low-grade inflammation and a host of age-related diseases. Recent evidence suggests that the clearance of senescent cells alleviates chronic inflammation and its associated dysfunction and diseases. However, the effect of this intervention on metabolic function in old age remains poorly understood.

Here, we demonstrate that dasatinib and quercetin (D&Q) have senolytic effects, reducing age-related increase in senescence-associated β-galactosidase, expression of p16 and p21 gene and P16 protein in perigonadal white adipose tissue (pgWAT). This treatment also suppressed age-related increase in the expression of a subset of pro-inflammatory SASP genes (mcp1, tnf-α, il-1α, il-1β, il-6, cxcl2, and cxcl10), crown-like structures, abundance of T cells and macrophages in pgWAT. In the liver and skeletal muscle, we did not find a robust effect of D&Q on senescence and inflammatory SASP markers.

Although we did not observe an age-related difference in glucose tolerance, D&Q treatment improved fasting blood glucose and glucose tolerance in old mice that was concomitant with lower hepatic gluconeogenesis. Additionally, D&Q improved insulin-stimulated suppression of plasma NEFAs, reduced fed and fasted plasma triglycerides, and improved systemic lipid tolerance. Collectively, results from this study suggest that D&Q attenuates adipose tissue inflammation and improves systemic metabolic function in old age. These findings have implications for the development of therapeutic agents to combat metabolic dysfunction and diseases in old age.