Advanced Glycation End-Products and Metabolomics Are Independently Associated With Frailty: The Longitudinal Doetinchem Cohort Study

Skin autofluorescence (SAF), reflecting advanced glycation endproducts' accumulation in tissue, has been proposed as a noninvasive aging biomarker. Yet, SAF has not been compared with 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 2 382 Doetinchem Cohort Study participants' (aged 46.0-85.4) cross-sectional data, of whom 1 654 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.