PR002921 (Project)

Description:Mitochondrial dysfunction is a key hallmark of aging and contributes to the age-related loss of metabolic plasticity. Although genetic disruptions of mitochondrial integrity can cause premature aging, the mechanisms underlying the natural aging of mitochondria remain poorly understood. Using proteomics, lipidomics, genetics, and functional assays in wild-type C. elegans and the long-lived mitochondrial mutants clk-1(qm30) and isp-1(qm150), molecular pathways were identified that support longevity despite sustained mitochondrial inefficiency. Notably, these findings, together with complementary transcriptomic and metabolomic analyses in humans, revealed an age-associated decline in phosphatidylcholine (PC) synthesis as a key driver of mitochondrial network disruption and dysfunction during normal aging. Importantly, dietary supplementation to increase PC levels restored mitochondrial integrity in aged nematodes and maintained metabolic plasticity in human cell culture models.