Milot Emmanuel, Morissette-Thomas V, Li Qing, Fried Linda P, Ferrucci Luigi, Cohen Alan A
Department of Chemistry, Biochemistry and Physics, Université du Québec à Trois-Rivières, 3351 boul. des Forges, CP 500, Trois-Rivières, QC, G9A 5H7, Canada.
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.
Mech Ageing Dev. 2014 Nov-Dec;141-142:56-63. doi: 10.1016/j.mad.2014.10.001. Epub 2014 Oct 20.
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.
机制学和进化学观点均认为衰老涉及生物体中多个相互关联的生化网络。具体而言，稳态生理失调（PD）假说认为衰老是由关键调节过程的逐渐崩溃所致。然而，关于PD如何随年龄变化并影响健康的具体细节尚不清楚。通过使用一种最近验证的PD测量方法，该方法涉及根据生物标志物数据计算多变量距离（DM），我们发现PD轨迹可预测死亡率、衰弱以及慢性疾病（癌症、心血管疾病和糖尿病）。具体来说，失调（即失调率）的个体斜率每增加一个单位，相关结局的相对风险范围为1.20至1.40。我们通过使用两套基于明显不同标准选择的生物标志物进行重复分析，并针对死亡率在三项基于队列的纵向研究中进行验证，确认了这些结果。总体而言，效应大小（方向和大小）在不同数据集、生物标志物组和结局之间的一致性表明，DM与健康结局之间的正相关关系是在人类群体中发现的普遍现象。因此，对失调轨迹的研究应能为衰老生理学提供重要见解，并提供具有临床意义的结局预测指标。
