Time since menopause and a circulating metabolomic signature for sarcopenia risk: Data from 68,064 women from the UK...

Menopause-related metabolic alterations may increase susceptibility to sarcopenia, yet the longitudinal dimension of reproductive ageing-namely time since menopause-has not been investigated using an innovative metabolomic strategy that captures dynamic, multi-pathway metabolic changes and constructs a validated metabolomic signature related to time since menopause. We aimed (1) to identify a plasma metabolomic profile related to time since menopause, (2) to evaluate the independent associations of time since menopause and the metabolomic signature with sarcopenia and its components, and (3) to quantify the mediation effect exerted by this profile.

We analyzed 68,064 naturally postmenopausal women (4406 with sarcopenia) from the UK Biobank and validated findings in 5971 women with repeat assessments. Time since menopause was defined as baseline age minus age at natural menopause. Nuclear magnetic resonance spectroscopy was used to quantify 251 plasma metabolites. Elastic net regression was applied to derive a metabolomic signature related to time since menopause, which was validated by correlation analysis. Multivariable logistic regression estimated odds ratios (ORs) for sarcopenia, low strength, mass, and performance; mediation was assessed via bootstrapping.

Eighty-six metabolites spanning lipid, amino acid, and glycolytic pathways-closely linked to energy metabolism and protein homeostasis relevant to muscle physiology-comprised the signature related to time since menopause (baseline r = 0.27, P < 0.001). Each 5-year increase in time since menopause was associated with higher odds of sarcopenia (OR 1.13, 95% CI 1.09-1.16), and each 1-SD higher signature score was independently associated with sarcopenia (1.06, 1.02-1.10). The metabolomic signature mediated 13.3% of the association between time since menopause and sarcopenia.

A distinctive, multi-pathway metabolomic signature tracks time since menopause and partly mediates its association with sarcopenia. Reflecting coordinated dysregulation in lipid and amino acid metabolism, this signature may provide a molecular link between reproductive ageing and postmenopausal muscle decline and has potential utility as a non-invasive biomarker for early risk stratification.