Long-term dasatinib plus quercetin effects on aging outcomes and inflammation in nonhuman primates: implications for senolytic clinical trial design.
Alistaire D Ruggiero, Ravichandra Vemuri, Megan Blawas, Masha Long, Darla DeStephanis, Abigail G Williams, Haiying Chen, Jamie N Justice, Shannon L Macauley, Steven M Day, Kylie Kavanagh
Author Information
Alistaire D Ruggiero: Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Ravichandra Vemuri: Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Megan Blawas: Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Masha Long: Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Darla DeStephanis: Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Abigail G Williams: Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Haiying Chen: Department of Biostatistics and Data Science, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Jamie N Justice: Section of Gerontology and Geriatric Medicine, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Shannon L Macauley: Section of Gerontology and Geriatric Medicine, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Steven M Day: Section of Gerontology and Geriatric Medicine, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Kylie Kavanagh: Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC, USA. kkavanag@wakehealth.edu. ORCID
Cellular senescence increases with aging and results in secretion of pro-inflammatory factors that induce local and systemic tissue dysfunction. We conducted the first preclinical trial in a relevant middle-aged nonhuman primate (NHP) model to allow estimation of the main translatable effects of the senolytic combination dasatinib (D) and quercetin (Q), with and without caloric restriction (CR). A multi-systemic survey of age-related changes, including those on immune cells, adipose tissue, the microbiome, and biomarkers of systemic organ and metabolic health are reported. Age-, weight-, sex-, and glycemic control-matched NHPs (D + Q, n = 9; vehicle [VEH] n = 7) received two consecutive days of D + Q (5 mg/kg + 50 mg/kg) monthly for 6 months, where in month six, a 10% CR was implemented in both D + Q and VEH NHPs to induce equal weight reductions. D + Q reduced senescence marker gene expressions in adipose tissue and circulating PAI-1 and MMP-9. Improvements were observed in immune cell types with significant anti-inflammatory shifts and reductions in microbial translocation biomarkers, despite stable microbiomes. Blood urea nitrogen showed robust improvements with D + Q. CR resulted in significant positive body composition changes in both groups with further improvement in immune cell profiles and decreased GDF15 (p = 0.05), and the interaction of D + Q and CR dramatically reduced glycosylated hemoglobin A1c (p = 0.03). This work indicates that 6 months of intermittent D + Q exposure is safe and may combat inflammaging via immune benefits and improved intestinal barrier function. We also saw renal benefits, and with CR, improved metabolic health. These data are intended to provide direction for the design of larger controlled intervention trials in older patients.
