Beneficial effects of the senolytic cocktail, dasatinib and quercetin, on age-related vascular and metabolic dysfunction are lost in mice lacking T and B cells

Aging is an independent risk factor of arterial and metabolic dysfunction, although the mechanisms remain incompletely understood. Cellular senescence, a persistent cell cycle arrest, accompanies age-related arterial and metabolic dysfunction. Reducing senescence burden after treatment with the senolytic cocktail, dasatinib and quercetin (D&Q), improves age-related arterial and metabolic dysfunction, although the tissues and/or cell types involved in these beneficial effects are unknown. At steady state, T cells play a critical role in eliminating senescent cells and suppressing inflammation. Likewise, evidence exist that aged T cells promote multiorgan aging and age-related systemic dysfunction. Previously, we have shown that T lymphocytes promote age-related arterial and metabolic dysfunction. Together, these raise a key question whether the beneficial effects of senolytic drugs are mediated through aged T cells. Here, we sought to test the hypothesis that T cells mediate the beneficial effects of senolysis in old mice. To test this hypothesis, 27-mo. Rag-/- mice (D&Q: n = 4, vehicle: n = 3), that lack functional T and B lymphocytes, were treated with D (5 mg/kg) & Q (50 mg/kg) for 3 consecutive days in every 15 days for 3 months. Arterial stiffness, assessed by aortic pulse wave velocity, was higher in D&Q (n = 4) compared to vehicle (n = 3) treated old RAG-/- mice. (P = 0.03). Likewise, endothelium-dependent dilation (EDD) to acetylcholine, assessed using pressure myography, was lower in isolated mesenteric arteries of the D&Q treated old RAG-/- mice compared to vehicle controls (P = 0.001). Differences in vasodilation between the treatment groups were abolished after L-NAME incubation, indicating that the impairment in EDD resulted from lower nitric oxide bioavailability in the D&Q treated RAG-/- mice (P = 0.73). Glucose (2 g/kg body mass, IP, GTT) and insulin (1 U/kg body mass, IP, ITT) tolerance tests were performed in fasted (4-6 hr) mice to assess systemic metabolic function. There were no differences in glucose or insulin tolerance between the D&Q (n = 4) and vehicle (n = 3) treated old RAG-/- mice(P = 0.65 & 0.33). These results suggest that the beneficial effects of senolytic treatment in old mice may require T and/or B cells. Future studies could employ the adoptive transfer of T cells from control mice to Rag-/- mice as well as antibody mediated T cell depletion in combination with senolytic treatment to explore the necessity of T cells in the beneficial effects of senolysis. NIA. Grant Numbers: R01 AG048366, R01 AG050238, R01 AG060395U.S. Department of Veterans Affairs. Grant Numbers: I01 BX002151, I01 BX004492 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.