Mental well-being relates to multitudinous lifestyle behaviours and morbidities and underpins healthy aging. Thus far, causal evidence on whether and in what pattern mental well-being impacts healthy aging and the underlying mediating pathways is unknown. Applying genetic instruments of the well-being spectrum and its four dimensions including life satisfaction, positive affect, neuroticism and depressive symptoms (n = 80,852 to 2,370,390), we performed two-sample Mendelian randomization analyses to estimate the causal effect of mental well-being on the genetically independent phenotype of aging (aging-GIP), a robust and representative aging phenotype, and its components including resilience, self-rated health, healthspan, parental lifespan and longevity (n = 36,745 to 1,012,240). Analyses were adjusted for income, education and occupation. All the data were from the largest available genome-wide association studies in populations of European descent. Better mental well-being spectrum (each one Z-score higher) was causally associated with a higher aging-GIP (β [95% confidence interval (CI)] in different models ranging from 1.00 [0.82–1.18] to 1.07 [0.91–1.24] standard deviations (s.d.)) independent of socioeconomic indicators. Similar association patterns were seen for resilience (β [95% CI] ranging from 0.97 [0.82–1.12] to 1.04 [0.91–1.17] s.d.), self-rated health (0.61 [0.43–0.79] to 0.76 [0.59–0.93] points), healthspan (odds ratio [95% CI] ranging from 1.23 [1.02–1.48] to 1.35 [1.11–1.65]) and parental lifespan (1.77 [0.010–3.54] to 2.95 [1.13–4.76] years). Two-step Mendelian randomization mediation analyses identified 33 out of 106 candidates as mediators between the well-being spectrum and the aging-GIP: mainly lifestyles (for example, TV watching and smoking), behaviours (for example, medication use) and diseases (for example, heart failure, attention-deficit hyperactivity disorder, stroke, coronary atherosclerosis and ischaemic heart disease), each exhibiting a mediation proportion of >5%. These findings underscore the importance of mental well-being in promoting healthy aging and inform preventive targets for bridging aging disparities attributable to suboptimal mental health.

心理健康与多种生活方式和疾病有关，是健康老龄化的基础。到目前为止，关于心理健康是否以及以何种模式影响健康老龄化以及潜在的中介途径的因果证据尚不清楚。应用幸福谱及其四个维度（包括生活满意度、积极情感、神经质和抑郁症状）的遗传工具（ n = 80,852 至 2,370,390），我们进行了两样本孟德尔随机化分析，以估计心理健康的因果效应关于与遗传无关的衰老表型（aging-GIP），这是一种稳健且具有代表性的衰老表型，其组成部分包括复原力、自评健康状况、健康寿命、父母寿命和长寿（ n = 36,745 至 1,012,240）。分析针对收入、教育和职业进行了调整。所有数据均来自欧洲血统人群中最大的可用全基因组关联研究。更好的心理健康谱（每个Z得分更高）与更高的老化 GIP 存在因果关系（ β [95% 置信区间 (CI)]，在不同模型中范围从 1.00 [0.82–1.18] 到 1.07 [0.91– 1.24]标准差（sd））独立于社会经济指标。复原力（ β [95% CI] 范围为 0.97 [0.82–1.12] 至 1.04 [0.91–1.17] sd）、自评健康状况（0.61 [0.43–0.79] 至 0.76 [0.59–0.93]）也存在类似的关联模式。点）、健康寿命（比值比 [95% CI] 范围为 1.23 [1.02–1.48] 至 1.35 [1.11–1.65]）和父母寿命（1.77 [0.010–3.54] 至 2.95 [1.13–4.76] 年）。 两步孟德尔随机化中介分析确定了 106 名候选者中的 33 名是幸福谱和衰老 GIP 之间的中介：主要是生活方式（例如看电视和吸烟）、行为（例如药物使用）和疾病（例如，心力衰竭、注意力缺陷多动障碍、中风、冠状动脉粥样硬化和缺血性心脏病），每种疾病的中介比例为>5%。这些发现强调了心理健康在促进健康老龄化方面的重要性，并为缩小因心理健康状况不佳而导致的老龄化差异提供了预防目标。