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.

中文翻译：

---

生理失调的轨迹以一致的方式预测三个人群的死亡率和健康结果。

机械论和进化论的观点都认为衰老涉及生物体中多个集成的生化网络。特别是，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引起的。然而，目前对于帕金森病如何随年龄变化以及影响健康的具体情况尚不清楚。使用最近经过验证的 PD 测量方法，包括根据生物标志物数据计算多变量距离 (DM)，我们发现 PD 轨迹可以预测死亡率、虚弱和慢性疾病（癌症、心血管疾病和糖尿病）。具体而言，与个体斜率相关的结果的相对风险（即失调率）范围为每单位斜率 1.20-1.40。我们通过使用两组生物标记物重复分析来确认结果，这些生物标记物的选择标准明显不同，并且在三项纵向队列研究中，对于死亡率而言。总体而言，数据集、生物标志物套件和结果之间的效应大小（方向和幅度）的一致性表明，糖尿病与健康结果之间的正相关关系是整个人群中发现的普遍现象。因此，对失调轨迹的研究应该能够对衰老生理学产生重要的见解，并提供具有临床意义的结果预测因子。