Causal effects of senescence through intrinsic epigenetic age acceleration on age-related diseases: a Mendelian randomization study

Older age is associated with many diseases. However, it is unclear whether the biological mechanisms underpinning senescense (biological ageing) is a cause of age-related diseases (ARDs). In this Mendelian randomization study, we examined the causal effects of intrinsic epigenetic age acceleration (IEAA) - a process assumed downstream of senescence - on the occurrence of ARDs. In a metanalysis of 18 genome-wide association studies (GWAS) spanning 12 ARDs in ~27 million people of European ancestry (median per GWAS: 17’008 cases vs. 40’940 controls), IEAA-associated SNPs did not significantly increase the risk of ARDs as a group (odds-ratio (OR) = 0.99) nor of any individual ARD (OR range: 0.87-1.04). However, one SNP, rs2736099 on TERT, was significantly associated with 8 of 10 ARDs with increased risk for lung and ovarian cancer, atrial fibrillation, and benign prostatic hyperplasia and lower risk for Alzheimer’s disease, rheumatoid arthritis, cardiovascular artery disease and breast cancer. No associations between rs2736099 and known ARD risk factors were found strengthening the causal role of rs2736099-associated senescence. While IEAA was not found as a unifying cause of ARDs, senescence seems to cause some ARDs while preventing others through a mechanism only partially affecting IEAA and associated with rs2736099.