Disruption of the Circadian Rhythm Is Exacerbated by Aging and Ameliorated by Time- restricted Feeding

<title>Abstract</title> <bold>Background: </bold>Circadian rhythms exist across species, and circadian rhythm disorder (CRD) occurs in people of all ages and is prevalent in those with age-related neurodegenerative diseases. The gut microbiota changes with age and a significant proportion of gut microbes show circadian rhythms in their homeostasis. Dysregulation of gut microbial homeostasis is likewise a neurodegenerative disease trigger. <bold>Results: </bold>In this study, to investigate the relationship between aging, CRD, and the gut microbes, we created a model of CRD by controlling the light/dark cycle, and found that aging aggravated their cognitive impairment and mood disorders. This was accompanied by a loss of gut microbial homeostasis, impairment of the intestinal barrier, and systemic inflammation in aged mice with CRD. The abnormal expression pattern of circadian genes underpin the age-related expression pattern of ifi27l2, thereby exacerbating oxidative stress. In addition, time-restricted feeding (TRF) ameliorated the negative effects of CRD in aged mice by enriching <italic>Akkermansia_muciniphila</italic>and inhibiting the NOD-like signaling pathway. <bold>Conclusion: </bold>Aged mice show more severe impairments in response to stress, likely due to inflammation from gut microbes and circadian gene dysregulation. Maintaining a regular eating schedule can help reduce these effects.