The potential of Senolytics in transplantation

Abstract

Older organs provide a substantial unrealized potential with the capacity to close the gap between demand and supply in organ transplantation. The potential of senolytics in improving age-related conditions has been shown in various experimental studies and early clinical trials. Those encouraging data may also be of relevance for transplantation. As age-differences between donor and recipients are not uncommon, aging may be accelerated in recipients when transplanting older organs; young organs may, at least in theory, have the potential to 'rejuvenate' old recipients. Here, we review the relevance of senescent cells and the effects of senolytics on organ quality, alloimmune responses and outcomes in solid organ transplantation. This article is part of the Special Issue - Senolytics - Edited by Joao Passos and Diana Jurk.

Keywords: Aging; Immunosenescence; Old donors; SASP; Senescent cells; Senolytics; Transplantation.

Figure 1.. Potential Opportunities to Apply Senolytics in Organ Transplantation

(A) Donor: Senolytics may be administered prior to organ donation. When applied in living donors, a regimen with minimal to no side effects is desirable. (B) Graft: Treatment of the graft after organ procurement and prior to transplantation represents an attractive therapeutic intervention. Ex-vivo perfusion systems allowing for prolonged organ evaluation may not only support the treatment with senolytics but may also aide in monitoring treatment effects. (C) Recipient: Recipients can be treated with senolytics at the time of transplantation or in the immediate post-transplant period; interaction between senolytics and immunosuppressants need to be considered.

Figure 2.. Interaction of Senolytic and Immunosuppressive drugs

Members of the Src family including Lck and Fyn are involved in early TCR signal transduction. Both, Dasatinib and Glucocorticoids target Src family proteins. IP3 is the trigger for Ca²⁺ release from the endoplasmic reticulum (ER) promoting the entry of extracellular Ca²⁺ into the cell via calcium release-activated Ca²⁺ channels. Calmodulin bound to calcium activates calcineurin while promoting the transcription of IL-2 through the NFAT transcription factor. CNI inhibits calcineurin, thus suppressing dephosphorylations of NFAT. Panobinostat induces calcineurin degradation through inhibiting the chaperone function of heat shock protein 90. CD28 co-stimulation of the TCR phosphorylates and activates PI3K, thereby activating the PI3K/mTOR pathway. Rapamycin inhibits T cell proliferation by inhibiting the formation of mTORC1.