Intake of L-serine before bedtime prevents the delay of the circadian phase in real life.

BACKGROUND: It has been shown in laboratory experiments using human subjects that ingestion of the non-essential amino acid L-serine before bedtime enhances the advance of circadian phase induced by light exposure the next morning. In the present study, we tested the effect of ingestion of L-serine before bedtime on circadian phase in real life and whether its effect depends on the initial circadian phase. METHODS: The subjects were 33 healthy male and female university students and they were divided into an L-serine group (n = 16) and a placebo group (n = 17). This study was conducted in a double-blind manner in autumn and winter. After a baseline period for 1 week, the subjects took 3.0 g of L-serine or a placebo 30 min before bedtime for 2 weeks. Saliva was collected twice a week at home every hour under a dim light condition from 20:00 to 1 h after habitual bedtime. Dim light melatonin onset (DLMO) was used as an index of phase of the circadian rhythm. RESULTS: DLMO after intervention was significantly delayed compared to the baseline DLMO in the placebo group (p = 0.02) but not in the L-serine group. There was a significant difference in the amount of changes in DLMO between the two groups (p = 0.04). There were no significant changes in sleeping habits after intervention in the two groups. There were significant positive correlations between advance of DLMO and DLMO before intervention in the L-serine group (r = 0.53, p < 0.05) and the placebo group (r = 0.69, p < 0.01). There was no significant difference in the slopes of regression lines between the two groups (p = 0.71), but the intercept in the L-serine group was significantly higher than that in the placebo group (p < 0.01). The levels of light exposure were not significantly different between the two groups. CONCLUSIONS: Our findings suggest that intake of L-serine before bedtime for multiple days might attenuate the circadian phase delay in the real world and that this effect does not depend on the initial circadian phase. TRIAL REGISTRATION: This study is registered with University Hospital Medical Information Network in Japan (UMIN000024435. Registered on October 17, 2016).

l-Serine Enhances Light-Induced Circadian Phase Resetting in Mice and Humans.

Background: The circadian clock is modulated by the timing of ingestion or food composition, but the effects of specific nutrients are poorly understood.Objective: We aimed to identify the amino acids that modulate the circadian clock and reset the light-induced circadian phase in mice and humans.Methods: Male CBA/N mice were orally administered 1 of 20 l-amino acids, and the circadian and light-induced phase shifts of wheel-running activity were analyzed. Antagonists of several neurotransmitter pathways were injected before l-serine administration, and light-induced phase shifts were analyzed. In addition, the effect of l-serine on the light-induced phase advance was investigated in healthy male students (mean ± SD age 22.2 ± 1.8 y) by using dim-light melatonin onset (DLMO) determined by saliva samples as an index of the circadian phase.Results: l-Serine administration enhanced light-induced phase shifts in mice (1.86-fold; P < 0.05). Both l-serine and its metabolite d-serine, a coagonist of N-methyl-d-aspartic acid (NMDA) receptors, exerted this effect, but d-serine concentrations in the hypothalamus did not increase after l-serine administration. The effect of l-serine was blocked by picrotoxin, an antagonist of γ-aminobutyric acid A receptors, but not by MK801, an antagonist of NMDA receptors. l-Serine administration altered the long-term expression patterns of clock genes in the suprachiasmatic nuclei. After advancing the light-dark cycle by 6 h, l-serine administration slightly accelerated re-entrainment to the shifted cycle. In humans, l-serine ingestion before bedtime induced significantly larger phase advances of DLMO after bright-light exposure during the morning (means ± SEMs-l-serine: 25.9 ± 6.6 min; placebo: 12.1 ± 7.0 min; P < 0.05).Conclusion: These results suggest that l-serine enhances light-induced phase resetting in mice and humans, and it may be useful for treating circadian disturbances.