Serum dysregulation of serine and glycine metabolism as predictive biomarker for cognitive decline in frail elderly subjects

Abstract

Frailty is a common age-related clinical syndrome characterized by a decline in the function of multiple organ systems, increased vulnerability to stressors, and a huge socio-economic burden. Despite recent research efforts, the physiopathological mechanisms underlying frailty remain elusive and biomarkers able to predate its occurrence in the early stages are still lacking. Beyond its physical component, cognitive decline represents a critical domain of frailty associated with higher risk of adverse health outcomes. We measured by High-Performance Liquid Chromatography (HPLC) a pool of serum amino acids including L-glutamate, L-aspartate, glycine, and D-serine, as well as their precursors L-glutamine, L-asparagine, and L-serine in a cohort of elderly subjects encompassing the entire continuum from fitness to frailty. These amino acids are known to orchestrate excitatory and inhibitory neurotransmission, and in turn, to play a key role as intermediates of energy homeostasis and in liver, kidney, muscle, and immune system metabolism. To comprehensively assess frailty, we employed both the Edmonton Frail Scale (EFS), as a practical tool to capture the multidimensionality of frailty, and the frailty phenotype, as a measure of physical function. We found that D-serine and D-/Total serine ratio were independent predictors of EFS but not of physical frailty. Furthermore, higher levels of glycine, glycine/L-serine and D-/Total serine were associated with worse cognition and depressive symptoms in the frail group. These findings suggest that changes in peripheral glycine and serine enantiomers homeostasis may represent a novel biochemical correlate of frailty.

Fig. 1. Correlations between the serum levels of amino acids and Edmonton Frailty Scale (EFS) total score in the whole elderly cohort.

Blue lines and gray shadows represent the best-fit line and its 95% CI, respectively. *p < 0.05, age- and sex-adjusted partial correlation.

Fig. 2. Correlations between the serum amino acids concentrations and age in elderly cohort stratified in frail and non-frail groups according to EFS.

Blue lines and gray shadows represent the best fit line and its 95% CI, respectively. *p < 0.05; **p < 0.01, Spearman’s correlation test.

Fig. 3. Correlations between the serum amino acids concentrations and measures of global cognition in elderly cohort stratified in frail and non-frail groups according to EFS.

Blue lines and gray shadows represent the best-fit line and its 95% CI, respectively. *p < 0.05; **p < 0.01, age and sex-adjusted partial correlations. Abbreviations: MMSE Mini-Mental State Examination, MoCA Montreal Cognitive Assessment.