Dietary Curcumin And Caloric Restriction As Interventions For The Reversal Of Age Associated Functional Decline

Augmentation and exacerbation of oxidative stress and low-grade chronic systemic inflammation during mid-life has been proposed as modifiable causative factors for neurobehavioral decline reported with normal aging. Physiologically, the imbalance of pro-oxidants and endogenous antioxidants leads to an increase in tissue- damaging oxidative stress. Aging has also been associated with chronic systemic inflammation that can damage healthy tissues and diminish cognitive and motor capacity. The overall hypothesis of this project is that caloric restriction and dietary curcumin, via their strong anti-oxidant and anti-inflammatory properties; can delay the onset or ameliorate cognitive and motor decline in middle aged and aged mice respectively. Study 1: Fifteen month-old male C57BL/6 mice were tested as a model of sedentary mid-life obesity for the pilot study. They underwent dietary treatment for 12 weeks and were subjected to cognitive tests at the 8th week of treatment. Dietary treatments included regular chow fed ad libitum (AL), curcumin (1g/kg of diet) fed ad libitum (CURAL) and 30% to weight stable caloric restriction (CR). Mice were tested for spatial learning and cognitive flexibility testing. Blood was collected to measure inflammation and oxidative stress. Results from the pilot study indicated a significant weight loss and reduced adiposity in the CR group; whereas CURAL mice maintained stable weight throughout the treatment, consumed more food than the AL mice, and did not show a reduction of adipose tissue. However, both the CR and CURAL groups took fewer trials than AL to reach criterion during the reversal sessions of the active avoidance task, suggesting an improvement in cognitive flexibility. The AL mice had higher levels of CRP compared to CURAL and CR, and reduced glutathione as well as the GSH/GSSG ratio were increased during curcumin intake, suggesting a reducing shift in the redox state. Study 2: In the subsequent study, 15 and 20 month old female and male C57BL/6 mice were used as a normal aging model to study functional decline. This study included all of the dietary interventions from the pilot study and an additional combination diet of CR and curcumin (CURCR). Curcumin was added to the diet at 7g/kg of diet with mice under CURCR receiving 7.2g/kg of diet, adjusted to take difference in food intake into account. The mice underwent dietary treatments for 4 months, and cognitive and motor behavior tests were conducted at 8 weeks of treatment. Mice were tested on multiple tasks that are sensitive to age associated cognitive and motor dysfunction. Results from the second study indicated females to be more active than males. Mice under CR and CURCR performed better in the motor tests compared to their age matched controls, which included coordinated running, wire suspension and bridge walking. Cognitive flexibility was significantly better for middle-aged males under CR and CURAL compared to AL but not under CURCR, suggesting an antagonistic interaction. On the other hand, middle aged and aged female experimental groups did significantly better than AL. No interaction of CR and CUR was observed in aged males, with CURAL and CR yielding comparable benefits. None of the treatments had a significant effect on hippocampus- dependent rate of learning in middle age or the aged; however middle aged males under the CURCR intervention had poorer probe performance compared to their age matched controls. Data from both projects suggest that independent of weight loss; dietary curcumin and CR have positive effects on fronto-cortical functions in late middle age and senescence that could be linked to anti-inflammatory or antioxidant actions. These effects were similar across different behavioral tasks and were non-additive or antagonistic in a sex dependent manner, suggesting that they could involve the same or similar mechanisms including an influence of sex hormones. Therefore, curcumin intake may mimic the neurobehavioral outcomes of CR that could be age dependent, but the mechanism of action underlying the outcomes of the CR and curcumin combination treatments need to be further examined.