Biological aging and lifespan in men and women using a Mendelian randomization study

Identification of targets of intervention to promote lifespan is crucial given lifespan is an important measure of public health. Telomere length and epigenetic clocks are key biological markers of aging, whether they are targets of intervention in men or women is unclear. We examined their associations with sex-specific lifespan in a Mendelian randomization study.

We used genetic summary statistics of telomere length and lifespan (parental attained age and survival to recruitment) from the UK Biobank (n = ~ 0.5 million, mean age = ~ 57 years) and of epigenetic clocks (GrimAge, PhenoAge, HannumAge and Intrinsic epigenetic age acceleration) from a meta-analysis of 28 cohorts (n = 34,710). Using this data, we employed two-sample MR to estimate the causal effect of each aging biomarker on lifespan in men and women. Estimates were obtained using inverse variance weighting with sensitivity analysis.

There was no evidence that telomere length was associated with lifespan in men (0.17 years per standard deviation of log telomere length, 95% confidence interval (CI) -0.54 to 0.88, survival - 0.17 years, 95% CI -0.39 to 0.05) or in women (0.04, 95% CI -0.88 to 0.96), although telomere length was associated with poorer survival to recruitment in women (survival - 0.24 years, 95% CI -0.44 to -0.03). Associations of epigenetic clocks with lifespan and survival were null in both men and women. Sensitivity analysis gave similar estimates.

Telomere length and commonly used epigenetic clocks may not be an appropriate target for promoting lifespan. Instead, efforts to develop interventions for aging should target causal drivers of lifespan.