Extracellular vesicle-derived mitochondrial genes as potential biomarkers for brain aging in human

Aging significantly impacts brain function, and identifying reliable biomarkers for early detection of age-related neurodegeneration is crucial for improving diagnosis and treatment outcomes. This proof-of-principle study aims to evaluate the abundance of mitochondrial DNA (mtDNA) targets within plasma-derived extracellular vesicles (EVs) and to investigate whether they correlate with established biomarkers of brain aging, independent of chronological age and renal function. mtDNA copy number was quantified using absolute quantitative polymerase chain reaction (qPCR). Brain aging biomarkers were measured by enzyme-linked immunosorbent assay (ELISA). Multivariable regression analysis was performed to examine the associations between EV mitochondrial genes and aging biomarkers. A multi-biomarker model was developed to assess the performance of combined biomarkers in distinguishing between age groups. We observed that EV mitochondrial gene levels were significantly increased with age (p < .001). Levels of neurofilament light chain (NfL), amyloid-beta (Aβ42 and Aβ40), also showed significant age-related increases (p < .001). A multi-biomarker model combining EV mitochondrial genes and brain aging biomarkers showed the optimal performance in distinguishing older adults from younger individuals, with an area under the receiver operating characteristic (ROC) curve (AUC) significantly higher than that of any single biomarker (p < .01). These findings collectively indicate that EV-derived mitochondrial genes, in combination with other biomarkers like NfL, hold great potential as a noninvasive tool for early detection and monitoring of brain aging and neurodegenerative diseases.