*Purpose: Donor aging leads to increased chronic allograft vasculopathy (CAV) for unclear reasons. Here, we investigated whether impaired alterations in mitophagy, a mechanism to remove damaged mitochondria, contributes to aged-enhanced CAV.

*Methods: To determine if donor aging enhances CAV in mice, we heterotopically transplanted young (2-4 months of age) and aged (18 months) BALB/c cardiac allografts into young (2-4 months of age) C57BL/6 recipients, which were treated with peri-operative costimulatory blockade to avoid acute allograft rejection.

*Results: At 100 days post transplantation, histological examination found that aged donors exhibited increased vessel occlusion (50%) vs. young allografts (20%, p<0.05, n=4 / group). We next compared the vasculature of young and aged mice prior to transplantation and found that aged arteries and vascular smooth muscle cells (VSMC) secreted a 2-fold increase in inflammatory mediators, specifically IL-6 and galectin-3 (n = >6/group, p<0.05). Inducing senescence via irradiating VSMC from young mice also led to a three-fold increase in the secretion of galectin-3. Examination of the VSMC from aged and young mitophagy reporter mice (mtKeima mice) revealed that the age-elevations in galectin-3 were accompanied with impaired mitophagy, supporting the concept that that failure to efficiently remove mitochondria leads to galectin 3 secretion. To examine this further, we examined the regulation of galectin-3 and IL-6 in young mice deficient in the mitophagy protein, Parkin. Interestingly, we found that, relative to young wild-type mice, Parkin deficient mice exhibited two-fold increase in aortic levels of both galectin-3 and IL-6 (n=6-8/group, p<0.05).

*Conclusions: Our study has revealed that donor aging increases CAV in mice and suggests that this is due to impaired mitophagy of the donor vasculature leading to the secretion of the inflammatory mediators, galectin-3 and IL-6. Inhibition of these mediators could be a therapeutic strategy to reduce age-enhanced CAV, thus facilitating an increased utilization of older organs for transplantation.

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