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

Abstract

Billions 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.

New light on chemotherapy toxicity and its prevention

“…Resveratrol-copper and its mechanism of action Of the three deactivating agents for cfChPs that have been previously utilised in preclinical studies, namely, CNPs, DNAse I, and R-Cu, the latter has been proven to be the agent of choice for therapeutic use in humans [21]. This is primarily because R-Cu can be easily administered orally and has demonstrated little toxicity in preclinical and clinical studies, even after prolonged administration [22]. Resveratrol (R) is a nutraceutical that has been extensively studied because of its antioxidant properties [23].…”

Exploiting the damaging effects of ROS for therapeutic use by deactivating cell-free chromatin: the alchemy of resveratrol and copper

“…However, compelling recent evidence indicates that ageing is the result of the lifetime damaging effects of cfChPs on healthy cells which can be ameliorated by ROS generated by the administration of R-Cu. It has been recently reported that the prolonged oral administration of R-Cu can downregulate multiple biological hallmarks of ageing in brain cells of C57Bl/6 mice, including telomere shortening, amyloid deposition, apoptosis, inflammation, mitochondrial dysfunction, DNA damage, senescence, and aneuploidy ( Figure 2 ; Pal et al, 2022 ). In the same study, R-Cu administration was also associated with significant reductions in the levels of serum glucose, cholesterol, and C-reactive protein ( Pal et al, 2022 ).…”

“…It has been recently reported that the prolonged oral administration of R-Cu can downregulate multiple biological hallmarks of ageing in brain cells of C57Bl/6 mice, including telomere shortening, amyloid deposition, apoptosis, inflammation, mitochondrial dysfunction, DNA damage, senescence, and aneuploidy ( Figure 2 ; Pal et al, 2022 ). In the same study, R-Cu administration was also associated with significant reductions in the levels of serum glucose, cholesterol, and C-reactive protein ( Pal et al, 2022 ). An interesting observation was the differential effects of R-Cu between male and female mice on telomere shortening, which requires further study ( Pal et al, 2022 ).…”

Among Gerontogens, Heavy Metals Are a Class of Their Own: A Review of the Evidence for Cellular Senescence

“…In human lung fibroblasts, Cu induced SA-β-Gal expression and altered proteostasis [ 187 ]. Interestingly enough, treatment of Cu with the drug resveratrol decreased the expression of p16 INK4a in the brains of aged mice, as well as several other hallmarks of brain aging, suggesting a non-monotonic response to Cu in brain aging [ 200 ]. While there is strong evidence of Cu inducing senescence in cell culture, a potential anti-aging property of Cu highlights the knowledge gaps that exist for metals toxicity, cellular senescence, and aging.…”