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

Nature Human Behaviour (2024)Cite this article

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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.

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Fig. 1: Overview of the study design.
Fig. 2: UVMR estimates for the causal associations between mental well-being and aging phenotypes.
Fig. 3: UVMR and MVMR estimates for the causal associations between mental well-being and aging phenotypes adjusting for socioeconomic indicators.
Fig. 4: Selection process for mediators of the causal association between the well-being spectrum and the aging-GIP.
Fig. 5: Mediating role of each mediator in the causal association between the well-being spectrum and the aging-GIP.

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Data availability

All GWAS summary statistics analysed in this study are publicly available as shown in Table 1 and Supplementary Table 1 for download by qualified researchers. The GWAS data for mental well-being traits can be obtained from the GWAS catalogue38 (https://www.ebi.ac.uk/gwas/publications/30643256). The GWAS data for aging phenotypes can be retrieved or requested from the study authors at https://doi.org/10.7488/ds/2972 (the aging-GIP14), https://doi.org/10.6084/m9.figshare.9204998.v3 (frailty index42), http://ftp.ebi.ac.uk/pub/databases/gwas/summary_statistics/GCST006001-GCST007000/GCST006620 (self-rated health43), https://doi.org/10.5281/zenodo.1302861 (healthspan44), https://doi.org/10.7488/ds/2463 (parental lifespan45) and https://www.longevitygenomics.org/downloads (longevity46). All data generated in this study are included in the Supplementary Information.

Code availability

All the MR analyses were conducted using R packages TwoSampleMR (version 0.5.7), MVMR (version 0.4), MRPRESSO (version 1.0) and MRlap (version 0.0.3.0) in R software (version 4.3.1). Custom code that supports the findings of this study is available at https://github.com/yechaojie/mental_aging.

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Acknowledgements

This work was supported by the grants from the National Natural Science Foundation of China (82370820, 82088102, 91857205, 823B2014 and 81930021), the ‘Shanghai Municipal Education Commission–Gaofeng Clinical Medicine Grant Support’ from Shanghai Jiao Tong University School of Medicine (20171901 Round 2), and the Innovative Research Team of High-level Local Universities in Shanghai. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The authors are grateful to the participants of all the GWASs used in this manuscript and the investigators who made these GWAS data publicly available.

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  1. These authors contributed equally: Chao-Jie Ye, Dong Liu, Ming-Ling Chen.

Authors and Affiliations

  1. Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    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 & Tian-Ge Wang

  2. Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    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 & Tian-Ge Wang

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Contributions

C.-J.Y. and T.-G.W. contributed to the conception and design of the study. C.-J.Y. performed statistical analyses and drafted the manuscript. T.-G.W. critically revised the manuscript. D.L., M.-L.C. and T.-G.W. checked the statistical analysis and proofread the manuscript. T.-G.W., G.N., W.-Q.W. and C.-J.Y. obtained funding. All authors contributed to the acquisition or interpretation of data, proofreading of the manuscript for important intellectual content and the final approval of the version to be published. T.-G.W. is the guarantor of this work and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Corresponding authors

Correspondence to Wei-Qing Wang, Yu-Fang Bi or Tian-Ge Wang.

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Ye, CJ., Liu, D., Chen, ML. et al. Mendelian randomization evidence for the causal effect of mental well-being on healthy aging. Nat Hum Behav (2024). https://doi.org/10.1038/s41562-024-01905-9

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