Environmental factors are associated with human longevity, but their specificity and causality remain mostly unclear. By integrating the innovative “exposome” concept developed in the field of environmental epidemiology, this study aims to determine the components of exposome causally linked to longevity using Mendelian randomization (MR) approach. A total of 4587 environmental exposures extracting from 361,194 individuals from the UK biobank, in exogenous and endogenous domains of exposome were assessed. We examined the relationship between each environmental factor and two longevity outcomes (i.e., surviving to the 90th or 99th percentile age) from various cohorts of European ancestry. Significant results after false discovery rates correction underwent validation using an independent exposure dataset. Out of all the environmental exposures, eight age-related diseases and pathological conditions were causally associated with lower odds of longevity, including coronary atherosclerosis (odds ratio = 0.77, 95% confidence interval [0.70, 0.84], P = 4.2 × 10−8), ischemic heart disease (0.66, [0.51, 0.87], P = 0.0029), angina (0.73, [0.65, 0.83], P = 5.4 × 10−7), Alzheimer’s disease (0.80, [0.72, 0.89], P = 3.0 × 10−5), hypertension (0.70, [0.64, 0.77], P = 4.5 × 10−14), type 2 diabetes (0.88 [0.80, 0.96], P = 0.004), high cholesterol (0.81, [0.72, 0.91], P = 0.0003), and venous thromboembolism (0.92, [0.87, 0.97], P = 0.0028). After adjusting for genetic correlation between different types of blood lipids, higher levels of low-density lipoprotein cholesterol (0.72 [0.64, 0.80], P = 2.3 × 10−9) was associated with lower odds of longevity, while high-density lipoprotein cholesterol (1.36 [1.13, 1.62], P = 0.001) showed the opposite. Genetically predicted sitting/standing height was unrelated to longevity, while higher comparative height size at 10 was negatively associated with longevity. Greater body fat, especially the trunk fat mass, and never eat sugar or foods/drinks containing sugar were adversely associated with longevity, while education attainment showed the opposite. The present study supports that some age-related diseases as well as education are causally related to longevity and highlights several new targets for achieving longevity, including management of venous thromboembolism, appropriate intake of sugar, and control of body fat. Our results warrant further studies to elucidate the underlying mechanisms of these reported causal associations.

中文翻译：

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研究暴露组与人类寿命之间的因果关系：孟德尔随机化分析


环境因素与人类长寿有关，但其特异性和因果关系仍不清楚。通过整合在环境流行病学领域开发的创新“暴露组”概念，本研究旨在利用孟德尔随机化（MR）方法确定与长寿有因果关系的暴露组成分。评估了从英国生物库的 361,194 名个体中提取的总共 4587 项环境暴露，在暴露组的外源和内源领域。我们研究了每个环境因素与不同欧洲血统群体的两种长寿结果（即存活到第 90 或 99 个百分位年龄）之间的关系。使用独立暴露数据集对错误发现率校正后的显着结果进行了验证。在所有环境暴露中，八种与年龄相关的疾病和病理状况与较低的长寿几率存在因果关系，包括冠状动脉粥样硬化（比值比 = 0.77，95% 置信区间 [0.70, 0.84]，P = 4.2 × 10−8 ）、缺血性心脏病 (0.66, [0.51, 0.87], P = 0.0029)、心绞痛 (0.73, [0.65, 0.83], P = 5.4 × 10−7)、阿尔茨海默病 (0.80, [0.72, 0.89], P = 3.0 × 10−5)、高血压 (0.70, [0.64, 0.77], P = 4.5 × 10−14)、2 型糖尿病 (0.88 [0.80, 0.96], P = 0.004)、高胆固醇 (0.81, [0.72) ，0.91]，P = 0.0003）和静脉血栓栓塞（0.92，[0.87，0.97]，P = 0.0028）。调整不同类型血脂之间的遗传相关性后，较高水平的低密度脂蛋白胆固醇（0.72 [0.64，0.80]，P = 2.3 × 10−9）与较低的长寿几率相关，而高密度脂蛋白胆固醇则与较低的寿命相关。 (1.36 [1.13, 1.62], P = 0.001) 显示相反的情况。 基因预测的坐/站高度与寿命无关，而 10 岁时较高的相对身高与寿命呈负相关。较大的身体脂肪，尤其是躯干脂肪量，以及从不吃糖或含糖食物/饮料与长寿呈负相关，而受教育程度则相反。本研究支持一些与年龄相关的疾病以及教育与长寿存在因果关系，并强调了实现长寿的几个新目标，包括管理静脉血栓栓塞、适当摄入糖分和控制体脂。我们的结果需要进一步的研究来阐明这些报告的因果关系的潜在机制。