Background & aims
Systemic iron status affects multiple health outcomes, however its net effect on life expectancy is not known. We conducted a two-sample Mendelian randomization (MR) study to investigate the association of genetically proxied iron status with life expectancy.

Methods
Using genetic data from 48,972 individuals, we identified three genetic variants as instrumental variables for systemic iron status. We obtained genetic associations of these variants with parental lifespan (n = 1,012,240) and individual survival to the 90th vs. 60th percentile age (11,262 cases and 25,483 controls). We used the inverse-variance weighted method to estimate the effect of a 1-standard deviation (SD) increase in genetically predicted serum iron on each of the life expectancy outcomes.

Results
We found a detrimental effect of genetically proxied higher iron status on life expectancy. A 1-SD increase in genetically predicted serum iron corresponded to 0.70 (95% confidence interval [CI] −1.17, −0.24; P = 3.00 × 10−3) fewer years of parental lifespan and had odds ratio 0.81 (95% CI 0.70, 0.93; P = 4.44 × 10−3) for survival to the 90th vs. 60th percentile age. We did not find evidence to suggest that these results were biased by pleiotropic effects of the genetic variants.

Conclusions
Higher systemic iron status may reduce life expectancy. The clinical implications of this finding warrant further investigation, particularly in the context of iron supplementation in individuals with normal iron status.