OXIDATIVE STRESS AND FRAILTY: A SYSTEMATIC REVIEW AND BEST EVIDENCE SYNTHESIS Running title: oxidative stress and frailty

250/250) Objective: Oxidative stress (OS) is associated with accelerated aging. Previous studies have suggested a possible relationship between OS and frailty but this association remains unclear. We conducted a systematic review to investigate potential interactions between OS and frailty. Methods: A systematic literature search of original reports providing data on ‘OS and antioxidant’ parameters and frailty was carried out across major electronic databases from inception until May 2016. Cross-sectional/case control and longitudinal studies reporting data on the association between frailty and anti-oxidants-OS biomarkers were considered for inclusion. Results were summarized with a best-evidence based synthesis. Results: From 1,856 hits, 8 studies (cross-sectional/case control) were included (N=6,349; mean age of 75±12 years; 56.4% females). Overall, there were 588 (=9.3%) frail, 3,036 prefrail (=47.8%), 40 (=0.6%) pre-frail/robust, and 2,685 (=42.3%) robust subjects. Six crosssectional/case control studies demonstrated that frailty was associated with an increase in peripheral OS biomarkers including lipoprotein phospholipase A2 (studies=1), isoprostanes (studies=2), Malonaldehyde (studies=2), 8-hydroxy-20-deoxyguanosine (studies=2), derivate of reactive oxygen metabolites (studies=2), oxidized Glutathione/ Glutathione (studies=1), 4hydroxy-2,3-nonenal (studies=1), and protein carbonylation levels (study=1). In addition, preliminary evidence points to lower anti-oxidant parameters (vitamin C, E, α-tocopherol, biological anti-oxidant potential, total thiol levels) in frailty. Conclusion: Frailty and pre-frailty appear to be associated with higher OS and possibly lower anti-oxidant parameters. However, due to the cross sectional design, it is not possible to disentangle the directionality of the relationships observed. Thus, future high quality and in particular longitudinal research is required to confirm/refute these relationships and to further elucidate pathophysiological mechanisms.

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