A pro-oxidant combination of resveratrol and copper down-regulates multiple biological hallmarks of ageing and neurodegeneration in mice

Abstract

AbstractBillions of cells die in the body every day, and cell-free chromatin particles (cfChPs) which are released from them enter into the extracellular compartments of the body, including into the circulation. cfChPs are known to readily enter into healthy cells to damage their DNA and activate apoptotic and inflammatory pathways. We have hypothesized that lifelong assault on healthy cells by cfChPs is the underlying cause of ageing, and that ageing could be retarded by deactivating extra-cellular cfChPs. The latter can be effected by oxygen radicals that are generated upon admixing the nutraceuticals resveratrol and copper (R–Cu). The present study investigated whether prolonged administration of R–Cu would retard biological hallmarks of ageing. C57Bl/6 mice were divided into 3 equal groups; one group was sacrificed at age 3 months, and which acted as young controls. The remaining mice were allowed to age, and at age 10 months the experimental ageing group was given R–Cu by oral gavage twice daily for further 12 months at a dose of 1 mg/kg of R and 0.1 μg/kg of Cu. The control ageing group was given water by oral gavage twice daily for 12 months. Animals of both groups were sacrificed at age 22 months. R–Cu treatment led to reduction of several biological hallmarks of ageing in brain cells which included telomere attrition, amyloid deposition, DNA damage, apoptosis, inflammation, senescence, aneuploidy and mitochondrial dysfunction. R–Cu treatment also led to significant reduction in blood levels of glucose, cholesterol and C-reactive protein. These findings suggest that cfChPs may act as global instigators of ageing and neurodegeneration, and that therapeutic use of R–Cu may help to make healthy ageing an attainable goal.