title: Age-related frailty and its association with biological markers of ageing.
abstract: BACKGROUND
  The relationship between age-related frailty and the underlying processes that drive changes in health is currently unclear. Considered individually, most blood biomarkers show only weak relationships with frailty and ageing. Here, we examined whether a biomarker-based frailty index (FI-B) allowed examination of their collective effect in predicting mortality compared with individual biomarkers, a clinical deficits frailty index (FI-CD), and the Fried frailty phenotype.
  
  
  METHODS
  We analyzed baseline data and up to 7-year mortality in the Newcastle 85+ Study (n = 845; mean age 85.5). The FI-B combined 40 biomarkers of cellular ageing, inflammation, haematology, and immunosenescence. The Kaplan-Meier estimator was used to stratify participants into FI-B risk strata. Stability of the risk estimates for the FI-B was assessed using iterative, random subsampling of the 40 FI-B items. Predictive validity was tested using Cox proportional hazards analysis and discriminative ability by the area under receiver operating characteristic (ROC) curves.
  
  
  RESULTS
  The mean FI-B was 0.35 (SD, 0.08), higher than the mean FI-CD (0.22; SD, 0.12); no participant had an FI-B score <0.12. Higher values of each FI were associated with higher mortality risk. In a sex-adjusted model, each one percent increase in the FI-B increased the hazard ratio by 5.4 % (HR, 1.05; CI, 1.04-1.06). The FI-B was more powerful for mortality prediction than any individual biomarker and was robust to biomarker substitution. The ROC analysis showed moderate discriminative ability for 7-year mortality (AUC for FI-CD = 0.71 and AUC for FI-B = 0.66). No individual biomarker's AUC exceeded 0.61. The AUC for combined FI-CD/FI-B was 0.75.
  
  
  CONCLUSIONS
  Many biological processes are implicated in ageing. The systemic effects of these processes can be elucidated using the frailty index approach, which showed here that subclinical deficits increased the risk of death. In the future, blood biomarkers may indicate the nature of the underlying causal deficits leading to age-related frailty, thereby helping to expose targets for early preventative interventions.
authors.affiliation: Department of Medicine, Dalhousie University, Halifax, NS, B3H 2E1, Canada. arnold.mitnitski@dal.ca.
authors.forename: Arnold
authors.initials: A
authors.lastname: Mitnitski
authors.affiliation: Institute of Health and Society and Newcastle University Institute for Ageing, Newcastle upon Tyne, NE4 5PL, UK. joanna.collerton@ncl.ac.uk.
authors.forename: Joanna
authors.initials: J
authors.lastname: Collerton
authors.affiliation: Institute of Neuroscience and Newcastle University Institute for Ageing, Newcastle upon Tyne, NE4 5PL, UK. carmen.martin-ruiz@ncl.ac.uk.
authors.forename: Carmen
authors.initials: C
authors.lastname: Martin-Ruiz
authors.affiliation: Institute of Health and Society and Newcastle University Institute for Ageing, Newcastle upon Tyne, NE4 5PL, UK. carol.jagger@ncl.ac.uk.
authors.forename: Carol
authors.initials: C
authors.lastname: Jagger
authors.affiliation: Institute for Cell and Molecular Biosciences and Newcastle University Institute for Ageing, Newcastle upon Tyne, NE4 5PL, UK. t.vonzglinicki@ncl.ac.uk.
authors.forename: Thomas
authors.initials: T
authors.lastname: von Zglinicki
authors.affiliation: Division of Geriatric Medicine, Dalhousie University, Halifax, NS, B3H 2E1, Canada. kenneth.rockwood@dal.ca.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Rockwood
authors.affiliation: Institute for Cell and Molecular Biosciences and Newcastle University Institute for Ageing, Newcastle upon Tyne, NE4 5PL, UK. tom.kirkwood@ncl.ac.uk.
authors.forename: Thomas B L
authors.initials: TB
authors.lastname: Kirkwood
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000097:blood*; D015415:Biomarkers / Q000097:blood*; D001774:Blood Chemical Analysis; D005260:Female; D016330:Frail Elderly / Q000706:statistics & numerical data*; D015577:Geriatric Assessment / Q000379:methods*; D006801:Humans; D008297:Male; D012016:Reference Values
chemical_list: D015415:Biomarkers