For patients with irreversible end-stage organ failure, organ transplantation is the treatment of choice. Older organs represent an untapped potential to close the gap between demand and supply in organ transplantation. But older organs often get discarded because they are linked to increased senescence — when cells no longer grow and divide — and immune responses, thereby aggravating transplant outcomes.

Iske and colleagues from the Harvard Medical School published an article in Nature Communications testing how senolytics — molecules that clear senescent cells — affect heart transplants from older donors in rodents. They show that senolytics dampen age-specific immune responses and prolong the survival of old donor cardiac transplants comparable to young donor organs.

“Our data provide a rationale for considering clinical trials treating donors, organs, or recipients with senolytic drugs to optimize the use of organs from older donors, helping to close the gap between organ availability and the needs of the many patients currently on transplant waiting lists,” concluded the authors in the article.

Why do old organ transplants fail?

Increased donor age poses a significant risk for adverse transplant outcomes, such as more frequent rejections of kidney or heart transplants. Also, the recovery after inevitable ischemia-reperfusion injury — tissue damage caused when blood supply returns to tissue (reperfusion) after a period of lack of oxygen (ischemia) — caused by transplantation is compromised in older organs. Clinically, this translates into higher rates of delayed graft function.

These adverse transplant outcomes may be related to how aging is linked with increased senescent cell burden that is tied to chronic, low grade, sterile inflammation called inflamm-aging. Accumulation of senescent cells with aging has been shown to contribute to declining renal function and cardiac stress resilience.

Ischemia-reperfusion injury is of clinical relevance in numerous illnesses, particularly in the elderly. Understanding the underlying changes in tissues during stress-surveillance responses in aging is of critical clinical importance and highly relevant to multiple diseases and conditions, including transplantation. The relationships among senescent cell accumulation, outcomes of transplantation, and the potential to mitigate injury and augmented immunogenicity of older organs by targeting senescent cells have so far not been thoroughly explored.

Old donor organs renewed with senolytics

Iske and colleagues saw that ischemia-reperfusion injury in rodents induced a systemic increase of circulating mitochondrial DNA — a small circular chromosome found inside mitochondria that leak out of damaged, diseased, and dying cells. They then showed that this cell-free mitochondrial DNA promoted age-specific inflammatory responses mediated by dendritic cells, immune cells that detect foreign substances. Moreover, the researchers tracked down the root of this circulating mitochondrial DNA to senescent cells that accumulate with aging and augment the immune response to transplantation.

To test the clinical relevance of these findings, Iske and colleagues compared the levels of cell-free mitochondrial DNA in plasma samples of older (>55 years) and younger (<35 years) human organ donors. Notably, young organ donors had consistently lower plasma levels of cell free mitochondrial DNA compared with old donors. Also, when stimulating human dendritic cells with human circulating mitochondrial DNA, the researchers observed upregulation of the molecules critical for mounting alloimmune responses.

(Iske et al. 2020 | Nat Commun.) Old human organ donors had increased systemic levels of circulating mitochondrial DNA. Iske and colleagues analyzed genes (Mt-CO3 and Mt-ND6) contained in circulating mitochondrial DNA from samples of older (>55 years) and younger (<35 years) organ donors. This analysis shows that younger organs donors (black) had lower plasma levels compared with old donors (red).

Iske and colleagues then wanted to see the effects of two senolytics: the chemotherapeutic dasatinib and the natural, plant-based quercetin, which is found in a variety of foods including apples, berries, Brassica vegetables, capers, grapes, onions, shallots, tea, and tomatoes, as well as many seeds, nuts, flowers, barks, and leaves. In rodents, when they treated old donor animals with both the senolytics dasatinib and quercetin, they observed a reduction in senescent cells and cell-free mitochondrial DNA release. This, in turn, appeared to dampen age-specific immune responses. Notably, administration of either dasatinib or quercetin individually was less effective than the combination of these senolytics in reducing circulating mitochondrial DNA levels.

Critically, dasatinib and quercetin treatment prolonged the survival of heart tissue grafts from old donors to levels comparable from young donors. Moreover, most hearts from treated old donors (80%) survived the observation period (100 days), while organs from old untreated donors stopped working by 37 days. This indicates that these senolytic agents might eventually prove to be effective in reducing cellular senescence-induced organ failure, inflammation, and dysfunction related to transplanting organs from older donors.

(Iske et al. 2020 | Nat Commun.) Senolytics reduce senescent cells and circulating mitochondrial DNA levels, alleviate systemic inflammatory immune response after ischemia reperfusion injury, and prolong cardiac allograft survival. Treatment with Dasatinib and quercitin prior to renal ischemia reperfusion injury reduced systemic levels of circulating mitochondrial DNA in old mice substantially (B, top left). Moreover, the senescent cell marker p16Ink4a was significantly reduced in old mouse kidneys after treatment with senolytics (B, top right). Transplanting organs from old donors that had been treated with both Dasatinib and Quercitin into recipients that were treated with the immunosuppressive agent CTLA4-Ig resulted in comparable survival of hearts from old and young donor mice (E, bottom).

“Collectively, we identify accumulating cell-free mitochondrial DNA as a key factor in inflamm-aging and present senolytics as a potential approach to improve transplant outcomes and availability,” concluded the authors in the article. These findings emphasize the clinical potential of senolytics for enabling the use of organs from older donors for transplantation.