Circulating cell-free DNA and plasma nuclease activity in human aging

Circulating cell-free DNA (cfDNA) is an emerging biomarker of aging, but age-related changes in its abundance, oxidation, and plasma nuclease activity have rarely been examined together. We measured plasma cfDNA concentration and nuclease activity in 418 community-dwelling participants aged 7-95 years and quantified 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) in cfDNA from 333 participants. cfDNA concentration increased and nuclease activity decreased across ages 7-80 years, whereas participants aged 81-95 years showed lower cfDNA concentration and higher nuclease activity than the 61-80-year group. The cfDNA-to-nuclease activity ratio peaked at 61-80 years and declined thereafter. cfDNA 8-oxodG content increased with age and was highest in the oldest group. The estimated plasma concentration of DNA-bound 8-oxodG rose sharply up to approximately 45 years and then plateaued. An exploratory composite index integrating cfDNA concentration, oxidation, and nuclease activity increased up to approximately 45 years and subsequently stabilized. These cross-sectional findings identify coordinated age-related changes in cfDNA burden, oxidation, and extracellular nuclease activity and support further mechanistic studies of oxidized cfDNA turnover in human aging.