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Causal relationship between depression and aging: a bidirectional two-sample Mendelian randomization study

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Abstract

Background

The causal relationship and the direction of the effect between depression and aging remain controversial.

Methods

We used a bidirectional two-sample Mendelian randomization analysis to examine the relationship between depression and age proxy indicators. We obtained pooled statistics from genome-wide association studies (GWAS) on depression and the age proxy indicators. We employed five MR analysis methods to address potential biases and ensure robustness of our results, with the inverse variance weighted (IVW) method being the primary outcome. We also conducted outlier exclusion using Radial MR, MRPRESSO, and MR Steiger filters. Additionally, sensitivity analyses were performed to assess heterogeneity and pleiotropy.

Results

Our MR analysis revealed that depression causally leads to shortened telomere length (β = − 0.014; P = 0.038), increased frailty index (β = 0.076; P = 0.000), and accelerated GrimAge (β = 0.249; P = 0.024). Furthermore, our findings showed that the frailty index (OR = 1.679; P = 0.001) was causally associated with an increased risk of depression. Additionally, we found that appendicular lean mass (OR = 0.929; P = 0.000) and left-hand grip strength (OR = 0.836; P = 0.014) were causally associated with a reduced risk of depression. Sensitivity analyses demonstrated the robustness of our findings.

Conclusions

Our study provides evidence that depression contributes to the accelerated aging process, resulting in decreased telomere length, increased frailty index, and accelerated GrimAge. Additionally, we found that the frailty index increases the risk of depression, while appendicular lean mass and left-handed grip strength reduce the risk of depression.

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Availability of data and materials

Summary statistics for TL, FI, ALM, usual walking pace, MVPA, handed grip strength, and cognitive performance were derived from the IEU OpenGWAS Project at https://gwas.mrcieu.ac.uk/.Summary statistics for FA were downloaded from: http://fastgwa.info/.Summary statistics for depression were downloaded from FinnGen Consortium at https://www.finngen.fi/en/access_results.Summary statistics for epigenetic age acceleration measures of HannumAge, Intrinsic HorvathAge, PhenoAge, and GrimAge were downloaded from: https://datashare.is.ed.ac.uk/handle/10283/3645.

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Acknowledgements

The authors acknowledged The FinnGen consortium for contributing the data used in this work. We thank all the genetics consortiums for making the GWAS summary data publicly available.

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Authors and Affiliations

  1. Jiangxi Provincial People’s Hospital and The First Affiliated Hospital of Nanchang Medical College, Nanchang, China

    Xinxin Luo & Ling Liu

  2. Beijing University of Chinese Medicine, Beijing, China

    Zhichao Ruan

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LL and ZR conceived, initiated, and supervised the project. XL collected and analyzed the data, and wrote a draft of the manuscript. JH assisted in reviewing the relevant manuscripts. The authors read and approved the final manuscript.

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Correspondence to Ling Liu.

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Luo, X., Ruan, Z. & Liu, L. Causal relationship between depression and aging: a bidirectional two-sample Mendelian randomization study. Aging Clin Exp Res 35, 3179–3187 (2023). https://doi.org/10.1007/s40520-023-02596-4

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