Epigenetic age biomarkers and risk assessment in adult spinal deformity: a novel association of biological age with frailty and disability
Authors: Safaee Michael M. , Dwaraka Varun B. , Lee Justin M. , Fury Marissa , Mendez Tavis L. , Smith Ryan , Lin Jue , Smith Dana L. , Burke John F. , Scheer Justin K. , Went Hannah , Ames Christopher P. 
Published: December 2023

OBJECTIVE
Surgery for spinal deformity has the potential to improve pain, disability, function, self-image, and mental health. These surgical procedures carry significant risk and require careful selection, optimization, and risk assessment. Epigenetic clocks are age estimation tools derived by measuring the methylation patterns of specific DNA regions. The study of biological age in the adult deformity population has the potential to shed insight onto the molecular basis of frailty and to improve current risk assessment tools.

METHODS
Adult patients who underwent deformity surgery were prospectively enrolled. Preoperative whole blood samples were used to assess epigenetic age and telomere length. DNA methylation patterns were quantified and processed to extract 4 principal component (PC)–based epigenetic age clocks (PC Horvath, PC Hannum, PC PhenoAge, and PC GrimAge) and the instantaneous pace of aging (DunedinPACE). Telomere length was assessed using both quantitative polymerase chain reaction (telomere to single gene [T/S] ratio) and a methylation-based telomere estimator (PC DNAmTL). Patient demographic and surgical data included age, BMI, American Society of Anesthesiologists Physical Status Classification System class, and scores on the Charlson Comorbidity Index, adult spinal deformity frailty index (ASD-FI), Edmonton Frail Scale (EFS), Oswestry Disability Index, and Scoliosis Research Society-22r questionnaire (SRS-22r). Medical or surgical complications within 90 days of surgery were collected. Spearman correlations and beta coefficients (β) from linear regression, adjusted for BMI and sex, were calculated.

RESULTS
Eighty-three patients were enrolled with a mean age of 65 years, and 45 were women (54%). All patients underwent posterior fusion with a mean of 11 levels fused and 33 (40%) 3-column osteotomies were performed. Among the epigenetic clocks adjusted for BMI and sex, DunedinPACE showed a significant association with ASD-FI (β = 0.041, p = 0.002), EFS (β = 0.696, p = 0.026), and SRS-22r (β = 0.174, p = 0.013) scores. PC PhenoAge showed associations with ASD-FI (β = 0.029, p = 0.028) and SRS-22r (β = 0.159, p = 0.018) scores. PC GrimAge showed associations with ASD-FI (β = 0.029, p = 0.037) and SRS-22r (β = 0.161, p = 0.025) scores. Patients with postoperative complications were noted to have shorter telomere length (T/S 0.790 vs 0.858, p = 0.049), even when the analysis controlled for BMI and sex (OR = 1.71, 95% CI 1.07–2.87, p = 0.031).

CONCLUSIONS
Epigenetic clocks showed significant associations with markers of frailty and disability, while patients with postoperative complications had shorter telomere length. These data suggest a potential role for aging biomarkers as components of surgical risk assessment. Integrating biological age into current risk calculators may improve their accuracy and provide valuable information for patients, surgeons, and payers.