Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age

Abstract

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; all p ≤ 0.04). 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 (all p ≤ 0.04). 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 ( p = 0.001) and glucose tolerance ( p = 0.007) in old mice that was concomitant with lower hepatic gluconeogenesis. Additionally, D&Q improved insulin‐stimulated suppression of plasma NEFAs ( p = 0.01), reduced fed and fasted plasma triglycerides (both p ≤ 0.04), and improved systemic lipid tolerance ( p = 0.006). 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.

Cellular Senescence Contributes to Large Elastic Artery Stiffening and Endothelial Dysfunction With Aging: Amelioration With Senolytic Treatment

“…7 Physiological levels of cellular senescence are critical for many reasons (eg, cancer suppression 8 and optimal wound healing 9 ); however, excessive accumulation of senescent cells occurs in multiple tissues with aging. [10][11][12] This age-related buildup of senescent cells can induce tissue dysfunction, at least in part through the SASP, and may be involved in several age-related pathologies. 11,12 As such, cellular senescence may contribute to vascular oxidative stress, reduced NO bioavailability, adverse changes to the aortic ECM, and vascular dysfunction with aging.…”

Rejuvenation strategies share gene expression programs of reduced inflammation and downstream restored fatty acid metabolism

“…Moreover, several other studies conducting transcriptomic analysis have reported changes in these pathways in the context of aging 22 (reduced), cellular senescence 23,24 (enhanced), HP 25 (enhanced), and especially in the context of CR 18,26–28 (enhanced), where it is highly foreseeable. Recently, the senolytic agents dasatinib and quercetin were shown to have similar effects on both inflammation and metabolism in adipose tissue, using targeted assays 29 .…”

Pancreatic adenocarcinoma and aging: understanding the menace for better management

“…Increasing senolytic drugs, such as dasatinib and quercetin, have recently been discovered to remove senescent cells in several age-related disorders. [209][210][211][212][213][214] Further studies are warranted to develop novel strategies for the prevention and treatment of PDAC in elderly patients.…”