Sleep · 2026
Metabolomic biomarkers of rest-activity rhythms in older women: results from the Women's Health Initiative study.
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Zhang Lingxiao, Yeung Chris Ho Ching, Lee Kyoung A Viola, Shadyab Aladdin H, LaCroix Andrea, Stone Katie L, Yaffe Kristine, Hayden Kathleen M, Casanova Ramon, Rapp Stephen R, Chen Jiu-Chiuan, Baker Laura, Manson JoAnn E, Huang Yuan, Xiao Qian
Аннотация
STUDY OBJECTIVES: Prior research has suggested that disrupted and weakened rest-activity rhythms measured by accelerometry may be associated with risks of many diseases, including cardiometabolic diseases, cancer, and dementia, but the mechanisms underlying this are not fully understood. This study is the second of two studies aimed at using an untargeted approach to identify metabolomic markers associated with rest-activity rhythm characteristics and focuses on older women.
METHODS: The analysis included 688 women in the Women's Health Initiative. Rest-activity rhythms were characterized by parametric and non-parametric algorithms applied to accelerometry data. Metabolomics data were measured from fasting serum samples with ultra high-performance liquid-phase chromatography and gas chromatography coupled with mass spectrometry and tandem mass spectrometry. Associations between rest-activity rhythms and metabolomics were determined by multiple linear regression models and Ingenuity Pathway Analysis.
RESULTS: Of the 934 metabolites included, 280 showed an association (false discovery rate < 0.1) with one of the three primary rest-activity variables (pseudo F-statistic, intradaily variability, and interdaily stability). These metabolites represent a wide range of biochemical classes and metabolic pathways, including sulfur amino acids, fibrinopeptides, plasmalogens, amino sugar metabolites, and nucleotides. The PEX5 gene network was identified by the Ingenuity Pathway Analysis as the most significantly enriched genetic pathway in relation to rest-activity rhythms.
CONCLUSIONS: We found numerous metabolites and pathways that were associated with rest-activity rhythm variables in older women, suggesting a potentially wide-reaching role of diurnal behaviors in human metabolism and health. Statement of Significance In this metabolomics study in older women, we found a large number of metabolites that were associated with rest-activity rhythms. These metabolites represented a wide range of biochemical classes and metabolic pathways. This analysis also confirmed numerous metabolite associations we have recently found in a sample of older men in the Osteoporotic Fractures in Men study, lending further support to a wide-reaching role of circadian rhythms and diurnal behaviors in human health. To the best of our knowledge, our two studies were the first metabolomics investigations focusing on rest-activity rhythm characteristics. With further validation studies, we anticipate that findings from these studies will contribute to the broader endeavor to understand, diagnose, and treat circadian rhythm-related disorders, with potential benefits for human health.
METHODS: The analysis included 688 women in the Women's Health Initiative. Rest-activity rhythms were characterized by parametric and non-parametric algorithms applied to accelerometry data. Metabolomics data were measured from fasting serum samples with ultra high-performance liquid-phase chromatography and gas chromatography coupled with mass spectrometry and tandem mass spectrometry. Associations between rest-activity rhythms and metabolomics were determined by multiple linear regression models and Ingenuity Pathway Analysis.
RESULTS: Of the 934 metabolites included, 280 showed an association (false discovery rate < 0.1) with one of the three primary rest-activity variables (pseudo F-statistic, intradaily variability, and interdaily stability). These metabolites represent a wide range of biochemical classes and metabolic pathways, including sulfur amino acids, fibrinopeptides, plasmalogens, amino sugar metabolites, and nucleotides. The PEX5 gene network was identified by the Ingenuity Pathway Analysis as the most significantly enriched genetic pathway in relation to rest-activity rhythms.
CONCLUSIONS: We found numerous metabolites and pathways that were associated with rest-activity rhythm variables in older women, suggesting a potentially wide-reaching role of diurnal behaviors in human metabolism and health. Statement of Significance In this metabolomics study in older women, we found a large number of metabolites that were associated with rest-activity rhythms. These metabolites represented a wide range of biochemical classes and metabolic pathways. This analysis also confirmed numerous metabolite associations we have recently found in a sample of older men in the Osteoporotic Fractures in Men study, lending further support to a wide-reaching role of circadian rhythms and diurnal behaviors in human health. To the best of our knowledge, our two studies were the first metabolomics investigations focusing on rest-activity rhythm characteristics. With further validation studies, we anticipate that findings from these studies will contribute to the broader endeavor to understand, diagnose, and treat circadian rhythm-related disorders, with potential benefits for human health.