Arbeev Konstantin G, Bagley Olivia, Ukraintseva Svetlana V, Kulminski Alexander, Stallard Eric, Schwaiger-Haber Michaela, Patti Gary J, Gu Yian, Yashin Anatoliy I, Province Michael A
Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, North Carolina 27708, USA.
Department of Chemistry, Washington University in St. Louis, St. Louis, Missouri 63130, United States.
medRxiv. 2024 Jul 30:2024.07.29.24311176. doi: 10.1101/2024.07.29.24311176.
Studying relationships between longitudinal changes in omics variables and risks of events requires specific methodologies for joint analyses of longitudinal and time-to-event outcomes. We applied two such approaches (joint models [JM], stochastic process models [SPM]) to longitudinal metabolomics data from the Long Life Family Study focusing on understudied associations of longitudinal changes in lysophosphatidylcholines (LPC) with mortality and aging-related outcomes (23 LPC species, 5,790 measurements of each in 4,011 participants, 1,431 of whom died during follow-up). JM analyses found that higher levels of the majority of LPC species were associated with lower mortality risks, with the largest effect size observed for LPC 15:0/0:0 (hazard ratio: 0.715, 95% CI (0.649, 0.788)). SPM applications to LPC 15:0/0:0 revealed how the association found in JM reflects underlying aging-related processes: decline in robustness to deviations from optimal LPC levels, better ability of males' organisms to return to equilibrium LPC levels (which are higher in females), and increasing gaps between the optimum and equilibrium levels leading to increased mortality risks with age. Our results support LPC as a biomarker of aging and related decline in robustness/resilience, and call for further exploration of factors underlying age-dynamics of LPC in relation to mortality and diseases.
研究组学变量的纵向变化与事件风险之间的关系需要特定的方法来联合分析纵向和事件发生时间结局。我们将两种此类方法(联合模型[JM]、随机过程模型[SPM])应用于长寿家庭研究的纵向代谢组学数据,重点关注溶血磷脂酰胆碱(LPC)纵向变化与死亡率和衰老相关结局之间未被充分研究的关联(23种LPC种类,4011名参与者中每种有5790次测量,其中1431人在随访期间死亡)。JM分析发现,大多数LPC种类的水平较高与较低的死亡风险相关,LPC 15:0/0:0的效应量最大(风险比:0.715,95%置信区间(0.649, 0.788))。对LPC 15:0/0:0应用SPM揭示了JM中发现的关联如何反映潜在的衰老相关过程:对偏离最佳LPC水平的稳健性下降,雄性生物体恢复到平衡LPC水平(女性中较高)的能力更强,以及最佳水平与平衡水平之间的差距不断增大导致随着年龄增长死亡风险增加。我们的结果支持LPC作为衰老以及相关稳健性/恢复力下降的生物标志物,并呼吁进一步探索与死亡率和疾病相关的LPC年龄动态背后的因素。