Homeostatic dysregulation proceeds in parallel in multiple physiological systems
Li, Qing; Wang, Shengrui; Milot, Emmanuel; Bergeron, Patrick; Ferrucci, Luigi; Fried, Linda P.; Cohen, Alan
Abstract: An increasing number of aging researchers believes that multisystem physiological dysregulation may be a key biological mechanism of aging, but evidence of this has been sparse. Here, we used biomarker data on nearly 33 000 individuals from four large datasets to test for the presence of multi-system dysregulation. We grouped 37 biomarkers into six a priori groupings representing physiological systems (lipids, immune, oxygen transport, liver function, vitamins, and electrolytes), then calculated dysregulation scores for each system in each individual using statistical distance. Correlations among dysregulation levels across systems were generally weak but signiﬁcant. Comparison of these results to dysregulation in arbitrary ‘systems’ generated by random grouping of biomarkers showed that a priori knowledge effectively distinguished the true systems in which dysregulation proceeds most independently. In other words, correlations among dysregulation levels were higher using arbitrary systems, indicating that only a priori systems identiﬁed distinct dysregulation processes. Additionally, dysregulation of most systems increased with age and signiﬁcantly predicted multiple health outcomes including mortality, frailty, diabetes, heart disease, and number of chronic diseases. The six systems differed in how well their dysregulation scores predicted health outcomes and age. These ﬁndings present the ﬁrst unequivocal demonstration of integrated multi-system physiological dysregulation during aging, demonstrating that physiological dysregulation proceeds neither as a single global process nor as a completely independent process in different systems, but rather as a set of system-speciﬁc processes likely linked through weak feedback effects. These processes – probably many more than the six measured here – are implicated in aging.
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