Molecular biomarkers for frailty as prognostic predictors of postoperative outcomes in elderly glioblastoma patients

Abstract

Glioblastoma patients over the age of 65 are often underrepresented in clinical trials, which leads to treatment decisions frequently being based on subjective assessments of physical resilience. Chronological age is commonly used as a surrogate marker, although it inadequately reflects actual physiological capacity. This is particularly problematic in perioperative management, as comorbidities and age-related physiological changes can lead to prolonged recovery and increased risk of complications. Frailty is therefore increasingly recognized as a more accurate predictor of postoperative risk but is still often assessed subjectively and without standardized tools in clinical care. The aim of this study was to investigate the extent to which preoperative frailty screenings and molecular biomarkers may help predict postoperative outcomes. A particular focus was placed on the analysis of telomere length and DNA methylation-based markers as indicators of biological age. Patients were screened preoperatively using the G8 frailty score and the Groningen Frailty Indicator (GFI). In parallel, telomere length was assessed via Southern blot analysis, and epigenetic age was estimated using the GrimAge, PhenoAge, Hannum, and DunedinPACE clocks. Primary endpoints included discharge modality, defined as discharge to home versus institutional care, and the duration of hospital stay. The results showed that shorter telomere length and elevated extrinsic epigenetic age acceleration (EEAA), calculated using the Hannum clock, were associated with a non-significant trend toward longer postoperative hospitalization and a slightly increased likelihood of discharge to institutional care. Among the frailty screening tools, the G8 score showed a weak trend toward longer hospital stays, while the GFI tended to underestimate frailty in high-risk patients. No clear predictive value was observed for the other epigenetic aging measures. Nevertheless, both screening instruments identified relevant areas of concern, particularly polypharmacy, psychosocial burden, and functional limitations. In conclusion, frailty questionnaires provided valuable additional information for the Comprehensive Geriatric Assessment (CGA) in this study. High-risk patients should be specifically evaluated for the respective problem domains within the CGA framework, for example using instruments such as the Instrumental Activities of Daily Living (IADL), Cumulative Illness Rating Scale for Geriatrics (CIRS-G), and Timed Get-Up-and-Go test (TGUG).