TY - JOUR
T1 - Trajectories of physiological dysregulation predicts mortality and health outcomes in a consistent manner across three populations
AU - Milot, Emmanuel
AU - Morissette-Thomas, V.
AU - Li, Qing
AU - Fried, Linda P.
AU - Ferrucci, Luigi
AU - Cohen, Alan A.
N1 - Funding Information:
The authors thank Véronique Legault for assistance in data preparation. EM was supported by a Centre de recherche sur le vieillissement (Sherbrooke) postdoctoral fellowship. AAC is a member of the FRQ-S-supported Centre de recherche sur le vieillissement and Centre de recherche Étienne Le-Bel, and is a funded Research Scholar of the FRQ-S. This research was supported by CIHR grant nos. 110789 , 120305 , 119485 and by NSERC Discovery Grant no. 402079-2011 . This research was supported by the Intramural Research Program of the National Institute on Aging (LF).
Publisher Copyright:
© 2014 Elsevier Ireland Ltd.
PY - 2014/11/1
Y1 - 2014/11/1
N2 - 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.
AB - 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.
KW - Diseases
KW - Longitudinal trajectories
KW - Mahalanobis distance
KW - Mortality
KW - Physiological dysregulation
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U2 - 10.1016/j.mad.2014.10.001
DO - 10.1016/j.mad.2014.10.001
M3 - Article
C2 - 25454986
AN - SCOPUS:84949116267
SN - 0047-6374
VL - 141-142
SP - 56
EP - 63
JO - Mechanisms of Ageing and Development
JF - Mechanisms of Ageing and Development
ER -