Over the last decade (2010–2020), the population of older adults (aged ≥ 65 years) experienced the most substantial and rapid growth, reaching 16.8% of the total population. This demographic shift has led to an increase in the prevalence of older adults with end-organ failure, leading to increased rates of transplantation across all solid organ transplant categories in this age group. Health-related quality of life is significantly higher among older transplant recipients compared to older waitlisted patients. However, 5-year graft survival rates after living donor kidney transplant (LDKT) and deceased donor kidney transplant (DDKT) are lower for older adults (80.8% vs. 68%) compared to younger adults aged 18–34 (90% vs. 80.7%) [1]. Organ transplantation in older adults presents unique challenges, as immunosuppression to prevent graft rejection, combined with age-related immune dysfunction, further increases vulnerability to infections [2]. Patient survival and graft survival are critical metrics used to assess the success and longevity of organ transplants, both of which can be adversely impacted by infections. Globally, as the demand for organ transplants continues to increase among older adults, understanding the association between aging, immune senescence, and infections becomes increasingly essential. This editorial emphasizes the critical need for future studies on the relationship between aging and infections in older adults undergoing organ transplants and highlights a vital research area to enhance care and improve survival for this population.
Aging leads to a decline in the function of the immune system, a phenomenon known as “immune senescence” which impacts both innate and acquired immunity [3]. Hallmarks include reduced naïve T-cells and naïve B-cells and an increase in memory T-cells and memory B-cells [3, 4]. Consequently, immune senescence can limit the body’s ability to mount effective antibody and cellular responses to infections and vaccinations and can lead to a loss of control of persistent viral infections (e.g., cytomegalovirus [CMV]) [4]. Another key feature of immune senescence includes “inflammaging,” a proinflammatory condition associated with aging, marked by higher baseline levels of inflammatory cytokines [4]. Despite substantial research on immune senescence in immunocompetent hosts, our understanding of T-cell dysfunction in organ transplant recipients, especially regarding its differential impact on older versus younger recipients, is still evolving. A pilot study by Schaenman et al. showed a trend toward a higher frequency of T-cell immune senescence in kidney transplant (KT) recipients who experienced infections during the first year posttransplant [2]. Physiological changes associated with immune senescence can affect drug metabolism, potentially increasing the risk of over-immunosuppression in older recipients [5]. Thus, a key objective of personalized medicine should be to tailor immunosuppressive management to improve overall survival and graft survival in older recipients [5].
Immune senescence closely overlaps with frailty, a clinical syndrome characterized by reduced physiological reserve, making individuals more vulnerable to stressors [6]. Frailty and aging-associated syndromes (sarcopenia, cognition, nutrition, and depression) are more closely associated with biological age than chronologic age [7]. Frailty is associated with impaired immune responses in older age, likely due to immune senescence, and evidence suggests a complex interplay of both frailty and immune senescence with infections and impaired vaccine efficacy [8]. The prevalence of frailty is higher among older KT recipients compared with younger KT recipients (20.8% vs. 14.3%) [9], and has been linked to early hospital readmission [10], increased risk of graft loss, and death with a functioning graft [11]. Although frailty is a well-established risk factor for infections (e.g., CMV, recurrent urinary tract infections [UTIs]) in older healthy adults [12], its impact on posttransplant infections in older recipients remains largely unexamined, despite the significant burden of posttransplant infections in this patient population.
CMV has a significant impact on morbidity and mortality in organ transplant recipients. Aging has a significant impact on CMV, and is associated with higher rates of CMV reactivation and greater risk of CMV tissue invasive disease in older transplant recipients [13, 14]. CMV has been linked with frailty, impaired physical function [15], and impaired cognitive function in healthy older adults and in people living with HIV. CMV, a proinflammatory virus, is believed to contribute to “inflammaging” and accelerate immune senescence. Utilizing the Scientific Registry of Transplant Recipients (SRTR) database, we reported characteristics of CMV seropositive organ transplant recipients including older age, female sex, Hispanic, and Black race [16]. Prior studies have shown that CMV reactivations are significantly more frequent in older KT recipients compared with younger KT recipients [14]. Furthermore, an initial episode of CMV reactivation significantly increases the risk of subsequent episodes in older recipients. Frail older KT recipients (aged ≥ 60 years) demonstrated more than a twofold increased risk of CMV infection and higher infection-related admissions compared to nonfrail counterparts [17].
Routine frailty assessments at the time of organ transplant can help stratify older recipients at risk for infections and guide prophylaxis and immunosuppression strategies to mitigate infections and reduce readmissions. The abridged frailty phenotype for assessment of frailty was developed by simplifying the five components of the physical frailty phenotype [18]. It has been validated in KT recipients and can accurately predict waitlist mortality. Transplant providers should consider using the abridged frailty phenotype to evaluate frailty when time is limited.
CMV donor and recipient (D/R) status plays a critical role in the management and outcomes of organ transplant recipients. Leveraging the SRTR, we demonstrated the negative impact of CMV donor positive/recipient negative (D+/R−) serostatus on graft and patient survival in a paired deceased donor kidney cohort [19]. These findings align with previous studies that link CMV D+/R− serostatus with poorer graft and patient survival in kidney, liver, and thoracic organ transplant recipients. In this study, the relative risk of 1-year mortality was higher amongst middle-aged (41–64 years) CMV D+/R− DDKT recipients (HR = 1.34; CI = 1.20–1.49, p-value < 0.001) compared to middle-aged CMV D+/R+ middle-aged DDKT recipients [19]. While older CMV D+/R− DDKT recipients were at a higher relative risk for 1-year posttransplant mortality compared with older CMV D+/R+ DDKT recipients, the effect was less pronounced.
Belga et al. reported similar findings, noting that CMV D+/R− compared to CMV D−/R− lung transplant recipients had a higher risk of posttransplant mortality, with the effect amplified in older recipients (≥ 60 years) [20]. The association between CMV D+/R− status with graft survival and mortality underscores the critical need for future studies to further investigate the underlying mechanisms.
The unique intersection of aging, organ transplantation, and infections highlights critical research gaps that must be prioritized. Current standardized approaches to prophylaxis and treatment of infections in organ transplant recipients do not consider the impact of age. Addressing these challenges requires interdisciplinary collaboration among transplant infectious disease specialists, transplant medicine specialists, geriatricians, and transplant surgeons. Fostering collaboration across disciplines and prioritizing these research areas could guide the development of tailored preventive and therapeutic strategies, optimization of immunosuppressive protocols, and improved clinical outcomes for older recipients. Key areas of focus include investigating the association of aging syndromes, such as baseline frailty, physical function, and cognitive function with early posttransplant infections (e.g., CMV, shingles, lower respiratory tract infections, recurrent UTIs) in older recipients. Transplant physicians need validated tools to stratify infection risk in older recipients and determine when it is safe to discontinue prophylaxis and treatment. Ultimately, such research could enhance survival rates, quality of life, and healthcare practices for older recipients.
Funding
This work was funded by the National Institute of Aging (Grant numbers R01AG055781, R01AG077888, and K02AG076883 to [PI: McAdams-DeMarco] and 1K23AG073534-01 to [PI: Abidi]).
Footnotes
Conflicts of Interest
The authors declare no conflicts of interest.
Data Availability Statement
This is an invited editorial. No data are available except for what is published in the manuscript.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
This is an invited editorial. No data are available except for what is published in the manuscript.