The thymus is a bilobed organ in the anterior mediastinum that is the primary site for maturation of T cells. The cellular composition of thymus includes thymocytes (immature T cells) and thymic epithelial cells, which play a role in negative selection of alloreactive cells. T cells released by thymus are immunologically naïve until they recognize an antigen with high affinity. Antigen recognition together with costimulatory signals leads to their proliferation and differentiation into effector cells. A subset of effector cells survives long-term to provide immunological memory to the specific antigen. Thymus function declines with age, otherwise known as age-related thymus involution. Thymus involution leads to reduced proportions of thymocytes and thymic epithelial cells, increased perivascular space, and adipose tissue deposition in thymic compartments. Disruption of thymic architecture results in loss of naïve T cells and a relative increase in memory T cells, thereby leading to reduced T cell-capacity of recognizing diverse pathogen-derived antigens leading to increased susceptibility to infection (6). Thymic involution may also explain decrease in immune responses to vaccines (62).

T cell maturation requires T cell receptor rearrangement and results in the formation of T cell receptor excision circles (TRECs) (63, 64). TRECs are stable and non-replicative, and progressively diminish with cell divisions. TRECs are therefore a useful measure of thymic output. Recent thymic emigrants are identified by elevated copy numbers of TRECs, and TREC frequency declines with aging (22, 23). Studies have correlated loss of transplant recipient thymic function, as measured by decreased TREC frequency, with poor post transplantation outcomes including cancer (24) and viral infections (25). Pre-transplant thymic function is identified as independent risk factor for viral infection post solid organ transplantation (26).

Strategies to address thymus loss could potentially have a role in transplantation. Grafting thymus lobes from an allogeneic donor into the neonatally thymectomized mice induced tolerance towards tissue antigens of the donor (65–67). Hence, concurrent thymus transplantation is a possible strategy to induce allospecific tolerance, while preserving immune function. Strategies to reverse thymus involution might also use thymostimulatory cytokines (68).

Cumulative antigenic exposure results in accumulation of terminally differentiated pro-inflammatory T cells with aging. Aged T cells display senescence hallmarks including short telomeres, DNA damage responses, replicative arrest, resistance to apoptosis, and secretion of pro-inflammatory cytokines (6). T cell aging is accelerated by chronic viral infections such as CMV, which drives the expansion of terminally differentiated CD8+ effector memory cells (T_EMRA) (69). T_EMRA cells exhibit markers of senescence while retaining the cytokine production and cytotoxicity potential of precursor cells (19). T_EMRA cells may have greater potential to drive allograft damage, as increased proportions of circulating T_EMRA correlate with higher risk of renal graft failure (20). In lung transplant recipients, CMV infection increases the risk of graft failure and susceptibility to infections (21). Hence, age-associated T cell defects driven by persistent viral antigenic stimulation may worsen clinical outcomes in transplantation recipients.

Tregs are professional anti-inflammatory cells that have a critical role in limiting allograft rejection (70). Aging correlates with a rise in inflammatory T cells at the expense of Tregs, The preponderance of data link robust Treg responses to improved outcomes, with the caveat that acute rejection drives a compensatory Treg expansion, limiting their utility as a biomarker (71). Tregs in older recipients transition to an effector phenotype in the context of IL-6 stimulation, a cytokine associated with senescent cells, Age-associated inflammation further drives dysregulation of microbiota in aged lungs perpetuating an inflammatory phenotype (72). Accordingly, therapeutic targeting IL-6, restoration of lung eubiosis by heathy diet and exercise harnessing the gut-lung axis, or directly administering in vivo expanded Treg have been proposed as strategies to improve graft survival. Notably, the limited proliferative capacity of Tregs from transplant recipients has proven a critical barrier to their development as a therapeutic (73).

B-cells and plasma cells generate antibodies in concert with T cell help. Such antibodies are key to immune responses to infections, but also drive antibody-mediated rejection. B cell antigen specificity and immunoglobulin type are refined through DNA rearrangements, known as class-switch recombination, which involves exchanging the IgM or IgD heavy chain region of the antibodies to an IgA, IgG, or IgE type, resulting in improved ability to eliminate pathogens, and somatic hypermutation, involving DNA mutations that generate antibodies with high antigen affinity. However, B cell precursors derive from the bone marrow, and an age-dependent shift in bone marrow myelopoiesis leads to impaired generation of B cell precursors (74). Extrinsic and cell intrinsic factors necessary for commitment, differentiation and maintenance of mature B cells are reduced with age (75, 76). Antibodies produced by aged B cells are less potent in class switching and somatic hypermutation (77), which may manifest as poor vaccination outcomes in elderly (7). As part of age-associated inflammation, B cells displaying a hyperreactive pro-inflammatory phenotype accumulate with age (78). Aged B cells respond in a B cell receptor independent innate fashion and contribute to inflammation and disease pathogenicity in autoimmune and autoinflammatory disorders (78).

The inflammatory phenotype of aged B cells may reduce allograft tolerance, as depletion of B cells delayed allograft rejection in aged mice and adoptive transfer of aged B cells worsened graft survival in young mice in a model of skin transplantation (79). However, an understanding the role of aged B cells in regulating outcomes in lung transplantation remains nascent.

Lung-resident alveolar macrophages exhibit a dual role in modulating inflammation. At steady state, alveolar macrophages clear apoptotic debris and subdue inflammation. These anti-inflammatory macrophages play a protective role in solid organ transplantation. For example, they promote the resolution of inflammation resulting from ischemia-reperfusion injury (80, 81). However, upon sensing of pathogens or tissue debris, alveolar macrophages are activated to release proinflammatory mediators which promote tissue injury (8, 82). Aging leads to impaired apoptotic clearance and anti-inflammatory cytokine production by macrophages thereby leading to prolonged inflammation and tissue injury (8, 83). Reduced reparative functions of aged alveolar macrophages potentiates inflammation potentially impairing graft survival.

Similarly, dendritic cells display an age-associated decline in function, evidenced by reduced phagocytosis, impaired antigen processing and presentation, reduced migration potential, diminished expression of co-stimulatory molecules and impaired cytokine production, leading to a dampened adaptive response in aged individuals and altered alloimmune responses in solid organ transplantation (6, 8).

Myeloid derived suppressor cells (MDSCs) are a heterogenous cell population of myeloid lineage with potent immunosuppressive activity. MDSCs are pathologically activated in inflammation, infection, and cancer. Aging skews the differentiation of hematopoietic progenitor cells towards myeloid lineage resulting in reduced lymphopoiesis and correspondingly increased proportions of myeloid derived suppressor cells (MDSCs). MDSCs inhibit T cell proliferation and are associated with improved graft survival in models of solid organ transplantation (84). Aged MDSCs express increased levels of cell cycle-associated senescent markers and can suppress T cells (85), potentiating their beneficial role in suppressing alloimmunity in solid organ transplantation.

Inherited disorders of mitochondrial function primarily manifest with myopathies, or disorders of skeletal muscle. Mitochondrial dysfunction can also manifest as encephalomyopathy, neuromuscular disorders, cardiac arrhythmias, diabetes, loss of vision and hearing, and stunted growth. The age-related loss of skeletal muscle, termed sarcopenia, is clinically defined as pathologically reduced muscle mass and strength and considered distinct from atrophy secondary to inactivity. Sarcopenia increases the risk of falls, fractures, physical disability, and death (97, 98). Sarcopenic muscle is characterized by increased mitochondrial DNA mutations, leading to the synthesis of dysfunctional respiratory chain components with reduced ATP synthesis capacity and increased ROS production (32). Physical exercise is potentially the most effective treatment strategy for sarcopenic individuals (99). Although the effect of exercise on sarcopenia is more complex than just muscle activation, exercise is associated with improved muscle mass, strength, and physical performance in older adults (33). Restoring metabolism of aged myeloid cells by targeting lipid signaling pathway may help decrease age-associated inflammation and restore mitochondrial homeostasis (100). Alternatively, controlled physical exercise promotes generation of ROS (101, 102) and simultaneous upregulation of antioxidant enzymes which counteract ROS generation (103). Exercise may help reduce the effects of oxidative stress in advanced age and thereby delay the onset of sarcopenia in physically active elderly population.

Older adults with sarcopenia have increased circulating cell-free mitochondria DNA (104). Stressed cells release endogenous contents that are recognized by pattern recognition receptors (PRRs) present on antigen presenting cells, induce an inflammatory response. Such endogenous moieties are referred to as danger associated molecular patterns (DAMPs). Mitochondrial DNA is capable of functioning as a DAMP when released into the cytosol as well as the circulation. Cell free mitochondrial DNA induces pro-inflammatory pathways to promote IFN-β release (105, 106). Furthermore, high levels of mitochondrial DAMPs in circulation are associated with increased severity of primary graft dysfunction, i.e., severe acute lung injury in first 72 h of transplantation which is a major cause of mortality in lung transplant recipients (107). Inhibition of receptors sensing damaged mitochondrial components rescued graft injury in a mouse orthotopic lung transplant model of primary graft dysfunction (34).

Systemic accumulation of ROS in sarcopenic patients may potentially contribute to immune activation (108). In a model of skin transplantation, mice undergoing regular exercise had improved graft survival (109). Interestingly, prolonged and exhaustive exercise promotes endotoxemia and systemic inflammation (110, 111). Thus, structured exercise interventions are worth investigating to address immune activation from mitochondrial dysfunction.

Beyond the role of systemic mitochondrial dysfunction in immune stimulation, dysfunctional mitochondria can directly drive immunosenescence through lymphocyte and myeloid cell dysregulation. Specifically, mitochondrial activities, including glycolysis and oxidative phosphorylation are implicated in T and B cell activation, differentiation, and proliferation, and mitochondrial impairment leads to a shift towards myeloid proliferation (112).

Comparisons of STS lung transplant recipients and those with normal telomere lengths have shown inconsistent results in terms of survival and graft outcomes such as primary graft dysfunction (PGD), acute cellular rejection (ACR), and CLAD. Newton et al. reported that STS lung transplant recipients had an increased rate of PGD and CLAD as well as with a nearly 11-fold increased risk of death compared to non-STS referents (116). Similarly, Courtwright et al. found that pre-transplant shortened telomere length was associated with leukopenia and decreased CLAD-free survival after lung transplant (118). Faust et al. found decreased telomere length was associated with leukopenia after transplant but was not associated with worse CLAD-free survival (12). In contrast, a more recent study of IPF lung transplant recipients found that telomere mutations and length was not associated with PGD, ACR, time to CLAD, or post-transplant survival (115). One potential reason for these inconsistencies is that short telomeres were not defined in the same way across all studies.

T-cell immunosenescence may be the predominant reason for the observation of less frequent acute rejection in STS lung transplant recipients. In a cohort of STS lung transplant recipients, there was an age-dependent decrease in acute rejection associated with evidence of immune aging, which was manifest as T cell differentiation, clonal expansion, and exhaustion (119). A similar immunosenescent phenotype has been observed in older renal transplant recipients, with short telomeres, evidence of T cell exhaustion, and decreased rates of acute rejection (120). IPF lung transplant recipients have relatively suppressed donor-specific effector and regulatory T cell responses at the time of transplant. This type of immunesenescence results in a state of anergy that is readily broken with strong cytokine stimulation, such as would be seen with infections (121). Thus, while lower rates of acute graft rejection may be seen in STS transplant recipients, these recipients are at continued risk of chronic rejection (122, 123).

Bone marrow reserves in STS lung transplant recipients are vulnerable. Cytopenias and bone marrow complications can emerge in the setting of antimetabolite or other immunosuppression medications, and certain antimicrobial and antiviral prophylaxis (124). Short recipient telomere length is a risk factor for clinically significant leukopenia (125). In a cohort with IPF, those who received lung transplantation were more likely to have bone marrow dysfunction requiring bone marrow biopsy (4% vs. 29%) (126). Management strategies to avert or mitigate bone marrow suppression may include dose modification of standard immunosuppression regimen by holding or decreasing antimetabolite therapies, holding viral polymerase inhibitors like valganciclovir, and using dapsone in place of trimethoprim/sulfamethoxazole for Pneumocystis prophylaxis (114).

Other than reduction of immunosuppression therapies and avoidance of myelosuppressive antimicrobial and antiviral prophylaxis, treatment for post-transplant cytopenia or bone marrow suppression is mainly supportive. Blood or platelet transfusions and granulocyte colony stimulating factor (GCSF) for neutropenia have been utilized. GCSF use has not been shown to increase risk for acute cellular rejection or CLAD when used in severely neutropenic patients (127). There is hesitation to use danazol in this population is due a lack of data and potential risk for MDS and AML (113). Bone marrow biopsy may be necessary to evaluate dyscrasias in certain cases given the risk for MDS and AML (126). Therefore, a multidisciplinary team including hematologists should be considered in the care of STS lung transplant recipients.

STS lung transplant recipients are at higher risk for herpes virus (HSV) and cytomegalovirus (CMV) infections due to T-cell immunodeficiency. Indeed, STS lung transplant recipients have up to a 5-fold increased risk for relapsing CMV viremia (13, 114, 128). As CMV viremia is a risk factor for CLAD, this telomere-dependent impairment of T cell immunity may contribute to increased CLAD risk in STS lung transplant recipients (43, 129). At the same time, several factors can complicate the treatment of CMV viremia in the STS population. STS lung transplant recipients are susceptible to CMV drug resistance and can develop myelosuppression from antiviral medications including ganciclovir and valganciclovir. Alternative treatments with foscarnet or cidofovir have limited utility in certain situations due to renal and bone marrow suppression and poor tolerance. Letermovir, a viral terminase inhibitor, has been approved for the prophylaxis of CMV infection in allogenic stem cell transplants. Letermovir has been studied off label for CMV prophylaxis in thoracic transplant recipients, including 37 lung transplant recipients, in whom it was well tolerated and effective. Without the side effect of bone marrow suppression, letermovir use may have facilitated antimetabolite therapy in certain number of patients (130). While there is concern that letermovir may be susceptible to CMV mutations conferring resistance, further study is warranted to determine whether letermovir could have a role for CMV prophylaxis, specifically in STS lung transplant recipients.

Iasella et al. (131) reported an increased risk for Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disorder (PTLD) in IPF lung transplant recipients, which was postulated to be secondary to STS immune dysfunction (131). When designing care protocol approaches to patients with known STS, consultation with infectious disease providers may be helpful to consider alternative agents to prevent and manage herpes viral infections (113).

Liver abnormalities have been reported in approximately 10% of STS patients. The combination of IPF, liver disease and bone marrow failure is a classic triad associated with severe STS (132). Gorgy et al. demonstrated that telomere shortening can also be linked to non-cirrhotic portal hypertension manifested as hepatopulmonary syndrome (HPS). STS patients with progressive HPS can present with clinical manifestations of severe hypoxemia, development of portal hypertension and complications including gastrointestinal bleeding from varices. Liver transplantation can reverse the hypoxemia in HPS however STS patients remain at risk for the development of progressive IPF (133). Several case reports describe combination of liver and lung transplantation in STS patients with end-stage IPF and cirrhosis with acceptable early outcomes (134, 135). Early screening for liver pathologies is recommended in patients with diagnosed STS in the pre-lung transplant period with appropriate laboratory evaluation, imaging, and subsequent referral to a hepatologist if liver disease or cirrhosis is suspected. Continued surveillance and monitoring for liver disease should be continued post transplantation.

Lung transplant recipients are at significantly increased risk of malignancy. Only 76% of double lung transplant recipients and 66% of single lung transplant recipients are free from non-skin malignancies by 15 years post-transplant, with a notable burden of lung cancer in single lung recipients (11). STS does not necessarily increase the risk of developing cancer in this cohort (116), but chronic immunosuppression appears to amplify the cancer risk associated with immune aging. Epigenetic dysregulation in combination with accumulation of DNA damage and senescent cells contribute to oncogenesis in the aged population, while proinflammatory cytokines can support tumor growth and metastasis (136).

Although the overall risk for cancer in STS is relatively low, IPF and STS can be associated with certain malignancies. IPF lung transplant recipients have increased risk for EBV-associated post-transplant lymphoproliferative disease, particularly after receiving alemtuzumab, in induction agent associated with immunosenescence (131). Outside of transplant, individuals with STS have increased risk for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). STS patients who develop MDS or AML may have concomitant lung fibrosis or liver disease or both making treatment decisions complex. The option for hematopoietic stem cell transplant and immunosuppressive regimens may be difficult due to risk for pulmonary injury and the choice for living related donor given the familial nature of STS may be limited (137). Combined bone marrow and lung transplantation has been reported with STS-associated bone marrow failure and ILD (138).

In sum, telomere length may be a potential biomarker pre-transplantation to assess the risk for various post-transplant complications, but the limited and inconsistent evidence from a series of single center studies must approached with caution. There is insufficient evidence to exclude lung transplant candidates from listing based on the presence of STS categorically, but there may be some circumstances where the severity of liver and/or bone marrow involvement may preclude the potential benefits of lung transplantation.