A recent article in the American Journal of Transplantation from researchers at the BARI, led by John Greenland and team, explores the biological underpinnings of how frailty, a state of increased vulnerability to stressors, influences lung transplantation. Lung transplantation can be a life-extending option for patients with end-stage lung disease, but success depends on more than just surgical technique or organ matching. Post-transplant outcomes are heavily influenced by the recipient’s overall resilience, particularly in older individuals where aging symptoms can complicate recovery. Although frailty is known to predict poorer outcomes in lung transplant recipients, the molecular drivers responsible for this effect are poorly understood. In this article, Kapse, et al. examine how key aging hallmarks, such as epigenetic changes, inflammation, telomere shortening, and anemia, relate to frailty in this population.
Frailty does not simply amplify all the cellular hallmarks of aging
To determine whether frailty in lung transplant recipients reflects broadly accelerated biological aging, the Greenland team analyzed pre-transplant peripheral blood from a matched cohort of 43 persistently frail and 43 non-frail control lung transplant recipients. As expected, both the Horvath (multi-tissue) and GrimAge (mortality-associated) epigenetic clocks correlate strongly with chronological age. However, neither clock showed a significant association with frailty status at baseline. “We were surprised,” said lead author Dr. Kapse. “These epigenetic clocks could identify patients’ ages and whether they had smoked, but didn’t reflect the frail recipients’ apparent age.” This lack of association is noteworthy, given that GrimAge is designed to predict lifespan and that these clocks have been linked to frailty in other populations. In a smaller subset with 1-year post-transplant follow-up samples, an intriguing divergence emerged: frail recipients exhibited an average GrimAge acceleration of +4.3 years over this interval, whereas non-frail recipients showed no change. While this raises the possibility that dynamic measures (change in epigenetic age over time) might outperform cross-sectional clocks for assessing frailty severity in high-stress clinical contexts, the team needed a better explanation for what drives frailty in this population.
Beyond global clocks, differential methylation analysis revealed frailty-associated DNA hypermethylation (suggesting repression) of genes in hedgehog signaling, angiogenesis, and select inflammatory pathways. Another surprising finding was the absence of systemic inflammation that might be expected with “inflamm-aging,” a kind of “sterile” inflammation that occurs during aging and is not in response to infection. In fact, plasma cytokine levels tended to be lower in frail patients on average.
Telomere biology provided a clearer signal: frail recipients had significantly shorter telomeres at baseline, despite similar rates of attrition over time, assessed cross-sectionally. Telomeres are protective caps at the ends of chromosomes that shorten with each cell division, and their excessive shortening is a well-established hallmark of aging. Telomere dysfunction is also an established cause for pulmonary fibrosis, which is a major indication for lung transplant. Thus, it makes sense that lung transplant populations would be enriched for other sequela of short telomere syndromes, which may include frailty. Specifically, short telomeres in muscle stem cells (satellite cells) could cause the low muscle mass (sarcopenia) that is associated with frailty. Whether telomere dysfunction-associated frailty is a modifiable risk factor remains an open question warranting future study.
Lastly, the researchers found that frail patients had lower hemoglobin and red blood cell count, indicating anemia. The anemia was not associated with a difference in serum iron or transferrin, but ferritin levels were higher and creatine was lower than in controls. This anemia of chronic illness may be another important and potentially modifiable risk factor.
This research highlights a need for tailored frailty assessments
End-stage lung diseases frequently produce phenotypic features – sarcopenia, fatigue, and exertional limitations – that overlap extensively with standard frailty criteria. This overlap risks conflating disease-specific impairment with systemic vulnerability, potentially leading to under-recognition of true frailty. Accurate classification of frailty is critical for transplant candidacy assessment, to understand who will actually benefit from this intensive procedure.
Current frailty tools rely almost exclusively on phenotypic measures and assume relatively uniform aging biology. Finding prominent roles for telomere attrition and anemia challenges this paradigm by demonstrating engagement of only some aging-associated biological processes. This context-specific pathobiology suggests that frailty in advanced lung disease may not be fully captured by generic tools that assume uniform aging mechanisms. Better frailty scores in the future might incorporate blood tests (hemoglobin, telomere assays) and adjusted physical scores to account for lung-specific limitations for a potentially more accurate way to stratify patients. Co-author and BARI researcher Dr. Jon Singer has been developing a lung transplant-specific frailty scale for better classification of patients undergoing lung transplantation. For the broader aging field, these findings underscore the value of stressor-rich clinical models for dissecting heterogeneity among aging hallmarks and refining biomarkers of resilience.
What’s next for the Greenland lab?
New approaches are needed to help frail individuals with end-stage lung diseases. Pre-habilitation with exercise-based therapies offers promise to improve survival and quality of life for this population. How these therapies impact aging-associated biological processes is a key open question. At the same time, biological aging mechanisms impact the transplanted lung as well, leading to chronic scarring that overlaps with the pulmonary fibrosis that may have caused the need for transplantation in the first place. The Greenland lab is hopeful that a detailed understanding of aging mechanisms in the transplanted lung may lead to improved outcomes for lung transplant recipients.