Breaking down causes, consequences, and mediating effects of age-related telomere shortening on human health

Abstract Telomeres represent repeated DNA sequences at the ends of chromosomes, which shorten with each cell division. Factors modulating telomere(definition) attrition and the health consequences thereof are not fully understood. To address this, we leveraged data from 326,363 unrelated UK Biobank participants of European ancestry and used linear regression and bidirectional univariable and multivariable Mendelian randomization (MR and MVMR) to elucidate the relationships between leukocyte telomere length (LTL) and 141 complex traits, including diseases, biomarkers, and lifestyle factors. We confirm that telomeres shorten with age and show a stronger decline in males than in females, which cannot be explained by hormonal or lifestyle differences. MR revealed 23 traits modulating LTL; e.g., smoking cessation and high educational attainment associated with longer LTL, while weekly alcohol intake, body mass index, urate levels, and female reproductive events, such as childbirth, associated with shorter LTL. We also identified 26 traits affected by LTL, with risk for cardiovascular, pulmonary, renal, and some autoimmune diseases being increased by short LTL, while longer LTL increased risk for other autoimmune conditions and cancers. Through MVMR, we show that LTL partially mediates the impact of educational attainment, body mass index, and female age at childbirth on lifespan. These results provide new insights into the biology of telomere regulation by shedding light on the modulators, consequences, and the mediatory role of telomere shortening, portraying an intricate relationship between LTL, diseases, lifestyle, and socio-economic factors.