Senescent Cells as a Mechanism for Worse Outcomes in Transplantation of Older Organs
Senescent cells accumulate with age in tissues throughout the body. They secrete a mix of signals that provokes chronic inflammation, disruption of tissue maintenance, and changes in cell behavior that lead to pathology. Targeted clearance of senescent cells has been shown to produce rejuvenation in mice, a reversal of many different age-related conditions, particularly those strongly linked to the chronic inflammation of aging. In this context, researchers here discuss the presence of greater numbers of senescent cells in older tissues as an important mechanism determining outcomes for patients following organ transplantation.
Organ transplantation is the treatment of choice for end-stage-organ failure. The supply of organs, however, is limited, resulting in prolonged waiting times with many patients dying or becoming too ill to be transplanted. Aging demographics have incrementally affected the deceased donor population with older donors showing the by far largest proportional increase. Organs from older donors are, at the same time, underutilized, frequently discarded or not even considered.
The most obvious strategy that may close the gap between demand and supply may thus be an optimized utilization of older organs from deceased donors. Increased donor age, at the same time poses a significant risk for adverse outcomes including more frequent rejections due to an augmented immunogenicity in aging. Most relevantly, older organs have shown compromised long-term graft outcomes with inferior graft survival rates in addition to increased rates of chronic allograft dysfunction in kidney, heart, and lung transplantation.
Senescent cells accumulate with aging and have been identified as critical in driving the immunogenicity of older organs linked to the accumulation of cell-free mitochondrial DNA that accelerate alloimmune responses. Recent evidence also suggests that senescent cells can induce a senescent phenotype in adjacent cells, a potential mechanism on how the engraftment of older organs may facilitate the spread of senescence. Depletion of senescent cells, at the same time, has been shown to ameliorate a wide range of age-associated disabilities and diseases.
Characteristically, senescent cells secrete a myriad of pro-inflammatory, soluble molecules as part of their distinct secretory phenotype that have been shown to drive senescence and age-related co-morbidities. Preliminary data show that the transplantation of old organs limits the physical reserve of recipient animals. Here, we introduce potential mechanisms and consequences of prompting bystander senescence and discuss clinically relevant aspects of senescent cell spread when transplanting older organs. Although speculative, age-disparate transplantation may also provide unique opportunities as the transplantation of young organs may contribute to rejuvenation.