AGEs mediate between muscular strength and psychotic symptoms: A birth cohort study

Muscular strength, assessed by handgrip, is a risk indicator for psychiatric disorders, including psychosis. However, the biological mechanisms underlying this association remain unclear.

Advanced glycation end products (AGEs) are derived from irreversible non-enzymatic modification of proteins and amino acids with reducing sugars. AGEs have been suggested to be responsible for the association between muscle strength and psychotic phenomena. Previous cross-sectional studies have reported an association between AGE accumulation and weak muscle strength. A recent longitudinal cohort study showed that AGEs can predict psychotic symptom trajectories among drug-naïve adolescents. Thus, there is a need to understand the role of AGEs in the association between muscle strength and psychosis to elucidate the biological mechanisms and early modifiable factors of psychosis.

In this study, we first evaluated the direction of the relationship between handgrip strength and urine levels of pentosidine, a representative AGEs in a population-based birth cohort of 1,542 adolescents at ages 12 and 14. Then, we examined the role of AGEs in the longitudinal association between handgrip strength and thought problems (TP), as a psychotic symptom indicator, in a subsample of 256 adolescents at ages 13 and 14.

As shown in Figure 1, an autoregressive cross-lagged model revealed that handgrip strength at age 12 negatively predicted pentosidine levels at age 14 (β=-0.20, p<0.001), whereas pentosidine levels at age 12 did not predict handgrip strength at age 14 (β=0.04, p=0.062). Moreover, pentosidine levels had a significant indirect effect on the relationship between handgrip strength and TP (standard indirect effect=-0.051, p=0.012), which remained significant after adjusting for gender and preceded TP and pentosidine levels (Figure 2). Thus, adolescents with low muscular strength are at a high risk of developing psychotic symptoms, which could be mediated by AGEs.

In conclusion, our study shows the association between low muscular strength in adolescents and later psychotic symptoms, which could be mediated by AGEs. Future studies need to examine whether interventions focused on muscular strength prevent the accumulation of AGEs and the development of psychosis.