Advanced glycation end-products and metabolomics are independently associated with frailty: the longitudinal Doetinchem Cohort Study.

Skin autofluorescence (SAF), reflecting advanced glycation end-products' accumulation in tissue, has been proposed as a non-invasive aging biomarker. Yet, SAF has not been compared to well-established blood-based aging biomarkers such as MetaboHealth in association with frailty. Furthermore, no previous study determined the longitudinal association of SAF with frailty. We used 2382 Doetinchem Cohort Study participants' (aged 46.0 to 85.4) cross-sectional data, of whom 1654 had longitudinal SAF measurements. SAF was measured using the AGE reader™. MetaboHealth was calculated on 1H-NMR-metabolomics. Linear regressions were used for the associations of SAF and MetaboHealth on the 36-deficit frailty index and logistic regressions for being pre-frail or frail as determined by the frailty phenotype. Longitudinal associations were determined by an interaction term between age and SAF in a linear mixed model. SAF and MetaboHealth were associated with higher odds of pre-frailty (odd ratios per standard deviation SAF: 1.21(1.10;1.32), MetaboHealth: 1.35(1.24;1.49)) and frailty (SAF: 1.70(1.41;2.06), MetaboHealth: 1.90(1.57;2.32)). When mutually adjusted, both aging biomarkers remained associated with pre-frailty (SAF: 1.16(1.05;1.27), MetaboHealth 1.33(1.21;1.46)) and frailty (SAF: 1.52(1.25;1.85), MetaboHealth: 1.75(1.43;2.14)). Additionally, SAF and MetaboHealth were associated with higher frailty index scores (percentage increase per standard deviation SAF:1.35(1.00;1.70), MetaboHealth: 1.87(1.54;2.20)), also after mutual adjustment (SAF: 1.02(0.68;1.37), MetaboHealth: 1.69(1.35;2.02)). SAF was also longitudinally associated with the frailty index (percentage per unit/year increase 0.12(0.07;0.16)). The mutual independence of SAF and MetaboHealth implies they capture distinct aspects of the aging process. Altogether, these findings emphasize SAF's clinical potential as an age-related decline biomarker, which could be further enhanced when combined with MetaboHealth.