Mendelian randomization identifies causal effects of major depressive disorder on accelerated aging
Zuxing Wang1, Yikai Dou2, Lili Chen1
1Sichuan Provincial Center for Mental Health, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, Chengdu 610072, China; Key Laboratory of Psychosomatic Medicine, Chinese Academy of Medical Sciences, Chengdu 610072, China.
Background:
Evidence links major depressive disorder (MDD) with aging, but it's unclear if MDD accelerates aging and what factors mediate this transition.
Methods:
Two-sample Mendelian randomization (MR) analyses were applied to estimate the causal association between MDD and frailty index (FI), telomere length (TL), and appendicular lean mass (ALM) from available genome-wide association studies in populations of European ancestry. Furthermore, we conducted mediation MR analyses to assess the mediating effects of 31 lifestyle factors or diseases on the causal relationship between MDD and aging.
Results:
MDD was significantly causally associated with increased FI (βIVW = 0.23, 95 % CI = 0.18 to 0.28, p = 1.20 × 10-17), shorter TL (βIVW = -0.04, 95 % CI = -0.07 to -0.01, p = 0.01), and decreased ALM (βIVW = -0.07, 95 % CI = -0.11 to -0.03, p = 3.54 × 10-4). The mediation analysis through two-step MR revealed smoking initiation (9.09 %), hypertension (6.67 %) and heart failure (5.36 %) mediated the causal effect of MDD on FI. Additionally, alcohol use disorders and alcohol dependence on the causal relationship between MDD and TL were found to be 17.52 % and 17.13 % respectively.
Limitations:
Confounding, statistical power, and Euro-centric focus limit generalization.
Conclusion:
Overall, individuals with MDD may be at a higher risk of experiencing premature aging, and this risk is partially influenced by the pathways involving smoking, alcohol use, and cardiovascular health. It underscores the importance of early intervention and comprehensive health management in individuals with MDD to promote healthy aging and overall well-being.
Insights
Major depressive disorder (MDD) may accelerate aging, increasing frailty and shortening telomere length. Smoking and alcohol use mediate this accelerated aging process, highlighting the need for early intervention in MDD patients.
Area of Science:
- Genetics
- Gerontology
- Psychiatry
Background:
- Major depressive disorder (MDD) is linked to aging.
- The potential for MDD to accelerate aging and the mediating factors remain unclear.
Purpose of the Study:
- To investigate the causal association between MDD and aging indicators.
- To identify lifestyle factors and diseases that mediate the relationship between MDD and aging.
Main Methods:
- Two-sample Mendelian randomization (MR) analyses were used.
- Genome-wide association studies in European ancestry populations were analyzed.
- Mediation MR analyses assessed 31 potential mediating factors.
Main Results:
- MDD was causally linked to increased frailty index (FI), shorter telomere length (TL), and decreased appendicular lean mass (ALM).
- Smoking initiation, hypertension, and heart failure mediated the MDD-FI link.
- Alcohol use disorders and dependence mediated the MDD-TL relationship.
Conclusions:
- Individuals with MDD face a higher risk of premature aging.
- Smoking, alcohol use, and cardiovascular health pathways partially mediate this risk.
- Early intervention and comprehensive management are crucial for individuals with MDD to promote healthy aging.
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