Mendelian randomization evidence for the causal effect of mental well-being on healthy aging

Chao-Jie Ye, Dong Liu, Ming-Ling Chen, Li-Jie Kong, Chun Dou, Yi-Ying Wang, Min Xu, Yu Xu, Mian Li, Zhi-Yun Zhao, Rui-Zhi Zheng, Jie Zheng, Jie-Li Lu, Yu-Hong Chen, Guang Ning, Wei-Qing Wang (), Yu-Fang Bi () and Tian-Ge Wang ()
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Chao-Jie Ye: Shanghai Jiao Tong University School of Medicine
Dong Liu: Shanghai Jiao Tong University School of Medicine
Ming-Ling Chen: Shanghai Jiao Tong University School of Medicine
Li-Jie Kong: Shanghai Jiao Tong University School of Medicine
Chun Dou: Shanghai Jiao Tong University School of Medicine
Yi-Ying Wang: Shanghai Jiao Tong University School of Medicine
Min Xu: Shanghai Jiao Tong University School of Medicine
Yu Xu: Shanghai Jiao Tong University School of Medicine
Mian Li: Shanghai Jiao Tong University School of Medicine
Zhi-Yun Zhao: Shanghai Jiao Tong University School of Medicine
Rui-Zhi Zheng: Shanghai Jiao Tong University School of Medicine
Jie Zheng: Shanghai Jiao Tong University School of Medicine
Jie-Li Lu: Shanghai Jiao Tong University School of Medicine
Yu-Hong Chen: Shanghai Jiao Tong University School of Medicine
Guang Ning: Shanghai Jiao Tong University School of Medicine
Wei-Qing Wang: Shanghai Jiao Tong University School of Medicine
Yu-Fang Bi: Shanghai Jiao Tong University School of Medicine
Tian-Ge Wang: Shanghai Jiao Tong University School of Medicine

Nature Human Behaviour, 2024, vol. 8, issue 9, 1798-1809

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41562-024-01905-9

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