Frailty and the role of inflammation, immunosenescence and cellular ageing in the very old: Cross-sectional findings from the Newcastle 85+ Study

► We confirm the importance of inflammation in frailty in a very old population. ► Limited evidence was found for role of immunosenescence in frailty in the very old. ► No frailty association was found for CMV or cellular ageing markers in the very old. ► Biomarker associations were generally consistent between Fried and Rockwood models. ► Difficulties in operationalizing the Fried model limit its utility in the very old. Age-related frailty is an increasing societal challenge with growing emphasis on identifying its underlying pathophysiology and prospects for intervention. We report findings from the first comprehensive study of frailty and biomarkers of inflammation, immunosenescence and cellular ageing in the very old. Using cross-sectional data from the Newcastle 85+ Study (n=845, aged 85), frailty was operationalized by the Fried and Rockwood models and biomarker associations explored using regression analysis. We confirmed the importance of inflammatory markers (IL-6, TNF-alpha, CRP, neutrophils) in frailty in the very old, previously established only in younger–old populations. Limited evidence was found for immunosenescence in frailty; although total lymphocyte count was inversely related, no association was found with the immune risk profile and the inverse associations observed with memory/naïve CD8 T and B cell ratios were in the opposite direction to that expected. We found no association with frailty in the very old for CMV sero-positivity, telomere length, markers of oxidative stress or DNA damage and repair. The Fried and Rockwood frailty models measure different albeit overlapping concepts yet biomarker associations were generally consistent between models. Difficulties in operationalizing the Fried model, due to high levels of co-morbidity, limit its utility in the very old.