title: Trajectories of physiological dysregulation predicts mortality and health outcomes in a consistent manner across three populations.
abstract: Mechanistic and evolutionary perspectives both agree that aging involves multiple integrated biochemical networks in the organism. In particular, the homeostatic physiological dysregulation (PD) hypothesis contends that aging is caused by the progressive breakdown of key regulatory processes. However, nothing is yet known about the specifics of how PD changes with age and affects health. Using a recently validated measure of PD involving the calculation of a multivariate distance (DM) from biomarker data, we show that PD trajectories predict mortality, frailty, and chronic diseases (cancer, cardiovascular diseases, and diabetes). Specifically, relative risks of outcomes associated with individual slopes in (i.e. rate of) dysregulation range 1.20-1.40 per unit slope. We confirm the results by replicating the analysis using two suites of biomarkers selected with markedly different criteria and, for mortality, in three longitudinal cohort-based studies. Overall, the consistence of effect sizes (direction and magnitude) across data sets, biomarker suites and outcomes suggests that the positive relationship between DM and health outcomes is a general phenomenon found across human populations. Therefore, the study of dysregulation trajectories should allow important insights into aging physiology and provide clinically meaningful predictors of outcomes.
authors.affiliation: Department of Chemistry, Biochemistry and Physics, Université du Québec à Trois-Rivières, 3351 boul. des Forges, CP 500, Trois-Rivières, QC, G9A 5H7, Canada.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Milot
authors.affiliation: PRIMUS Research Group, Groupe de recherche PRIMUS, Department of Family Medicine, University of Sherbrooke, CHUS-Fleurimont, 3001 12e Avenue North, Sherbrooke, QC J1H 5N4, Canada.
authors.forename: V
authors.initials: V
authors.lastname: Morissette-Thomas
authors.affiliation: PRIMUS Research Group, Groupe de recherche PRIMUS, Department of Family Medicine, University of Sherbrooke, CHUS-Fleurimont, 3001 12e Avenue North, Sherbrooke, QC J1H 5N4, Canada.
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.affiliation: Mailman School of Public Health, Columbia University, 722 West 168th Street, R1408, New York, NY, 10032, USA.
authors.forename: Linda P
authors.initials: LP
authors.lastname: Fried
authors.affiliation: Translational Gerontology Branch, Longitudinal Studies Section, National Institute on Aging, National Institutes of Health, Baltimore, MD 21225, USA.
authors.forename: Luigi
authors.initials: L
authors.lastname: Ferrucci
authors.affiliation: PRIMUS Research Group, Groupe de recherche PRIMUS, Department of Family Medicine, University of Sherbrooke, CHUS-Fleurimont, 3001 12e Avenue North, Sherbrooke, QC J1H 5N4, Canada. Electronic address: alan.cohen@usherbrooke.ca.
authors.forename: Alan A
authors.initials: AA
authors.lastname: Cohen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging; D002318:Cardiovascular Diseases / Q000401:mortality*; D002908:Chronic Disease; D003920:Diabetes Mellitus / Q000401:mortality*; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000401:mortality*
keywords: Diseases; Longitudinal trajectories; Mahalanobis distance; Mortality; Physiological dysregulation