*Purpose: Older organs represent an underutilized potential. Organ age, at the same time, augments alloimmune responses resulting into increased acute rejection rates. Senescent cells accumulate with aging and secrete a myriad of inflammatory cytokines that may promote senescence in neighboring cells. Here, we evaluated the hypothesis that senescent cells disseminate in recipients when transplanting older organs and delineated the potential of accelerating aging.

*Methods: Hearts from either young or old C57BL/6 (2 and 18 months) were transplanted into young syngeneic recipients. Solid organs and lymphoid tissue were collected from donors and recipients at sequential intervals after engraftment, assessing the accumulation and distribution of senescent cells and inflammatory products; systemic and local senescent associated secretory phenotype (SASP) derived molecules (mt-DNA, p16) were measured by qPCR. T cell and DC frequency and activation were tested by FACS and co-culturing experiments. In additional experiments, senolytics (Dasitinib and Quercetin, D&Q) were applied to young and old donor animals and cardiac transplants were performed in a model of strong histoincompatibility.

*Results: We detected an increased frequency of senescent cells in hearts, kidneys and skin of old donor mice (mean= 8,21% vs 0,3% in organs from young animals). Of relevance, young recipients of old cardiac allografts demonstrated increased frequencies of senescent cells (Post-operative day 30) localized in draining lymph nodes and livers (3,1-fold and 20.3 fold increase, p<0.01 and p<0.0001 compared to young recipients of young hearts); moreover, young recipients of old grafts also showed augmented systemic p16 levels indicating a spread of the senescent phenotype (3,45-fold increase, p< 0.05). As part of the SASP, isolated senescent cells released significantly increased amounts of mt-DNA (p<0.05) that promoted an extensive costimulatory molecule expression in old dendritic cells in-vitro with an augmented alloimmunity featuring Th17 and Th1 responses. Treatment of old donor animals with senolytics (D&Q) that have been shown to disable senescence-associated anti-apoptotic pathways (SCAPs) did not only clear senescent cells but also reduced mt-DNA and p16 levels in old animals (p=0.01 compared to young controls); senolytics also restricted the expression of IFN-γ and IL-17 on CD4⁺ T cells (P<0.001) and prolonged the survival of old cardiac allografts (P=.0.02).

*Conclusions: The accumulation of senescent cells in old organs accelerated alloimmune responses through augmented mt-DNA levels while promoting senescence in transplant recipients. Senolytics prevented an accelerated senescence and prolonged allograft survival providing a rationale to apply senolytics to donors or organs during preservation.

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