AbstractTelomere shortening has been associated with multiple age-related diseases such as cardiovascular disease, diabetes, and dementia. However, the biological mechanisms responsible for these associations remain largely unknown. In order to gain insight into the metabolic processes driving the association of leukocyte telomere length (LTL) with age-related diseases, we investigated the association between LTL and serum metabolite levels in 7,853 individuals from seven independent cohorts. LTL was determined by quantitative polymerase chain reaction and the levels of 131 serum metabolites were measured with mass spectrometry in biological samples from the same blood draw. With partial correlation analysis, we identified six metabolites that were significantly associated with LTL after adjustment for multiple testing: lysophosphatidylcholine acyl C17:0 (lysoPC a C17:0, p-value = 7.1 × 10⁻⁶), methionine (p-value = 9.2 × 10⁻⁵), tyrosine (p-value = 2.1 × 10⁻⁴), phosphatidylcholine diacyl C32:1 (PC aa C32:1, p-value = 2.4 × 10⁻⁴), hydroxypropionylcarnitine (C3-OH, p-value = 2.6 × 10⁻⁴), and phosphatidylcholine acyl-alkyl C38:4 (PC ae C38:4, p-value = 9.0 × 10⁻⁴). Pathway analysis showed that the three phosphatidylcholines and methionine are involved in homocysteine metabolism and we found supporting evidence for an association of lipid metabolism with LTL. In conclusion, we found longer LTL associated with higher levels of lysoPC a C17:0 and PC ae C38:4, and with lower levels of methionine, tyrosine, PC aa C32:1, and C3-OH. These metabolites have been implicated in inflammation, oxidative stress, homocysteine metabolism, and in cardiovascular disease and diabetes, two major drivers of morbidity and mortality.