One of the tests commonly used to evaluate the cognitive effects of caloric restriction (CR) is the Rey Auditory Verbal Learning Test (AVLT). Participants attempt to repeat as many words as possible from a list of 15 after a 30 minute delay, and greater recall is assumed to indicate better verbal memory. Witte et al. conducted the AVLT on individuals both before and after a schedule of CR. They found around a 28 +/- 6% increase in words remembered, which was a highly statistically significant difference. However, when Redman et al. conducted the AVLT on individuals after undergoing a schedule of CR, they found no significant improvements in verbal memory. One possible explanation for these conflicting findings is the degree of CR, which was a 30% reduction in calorie intake in Witte et al.’s study and only a 25% reduction in Redman et al.’s study. But the more likely explanation is age. Witte et al. studied men and women who were 50 to 80 years old, while Redman et al. studied men and women of ages 25 to 45, which is a much younger cohort.
One reason for the differential effects of CR due to age could be insulin signaling. Both Witte et al. and Redman et al. found an increase in insulin sensitivity following CR, but in Witte et al.’s older cohort, the percentage change in fasting insulin for each individual on CR was negatively correlated with his or her percentage improvements in verbal memory. Witte et al. note that a decline in insulin signaling has been associated with an increased propensity for age-related cognitive impairments such as in Alzheimer’s disease. One way that insulin signaling might cause this effect is by decreasing the ability of brain cells to resist damage from oxidative stress. As evidence for this, Hyun et al. note that CR serum has reduced levels of insulin and insulin-like growth factor 1, which contributes to its anti-oxidative damage phenotype. So, improvements in insulin sensitivity due to CR could promote the antioxidant effects shown by Hyun et al. that allow neurons to resist damage to membrane lipids and proteins. And since antioxidants are believed to have greater beneficial effects in preventing age-related declines (for example, see Galli et al.’s study of heat shock proteins), the cognitive effects of CR should be more pronounced in older cohorts.
Two findings favor this explanation. First, insulin sensitivity-related diseases such as type II diabetes can often lead to age-related cognitive decline. Consider insulin sensitivity as a continuum with CR on one extreme and type II diabetes on the other extreme. Then, the improvement in cognition due to CR and the decline in cognition due to type II diabetes are consistent ends of the same spectrum. Second, this explanation helps to consolidate the pleiotropic effects of the protein sirtuin 1 as a molecular link between insulin sensitivity and resistance to oxidative damage. Sirtuin 1 plays a role in metabolism and has been implicated in increasing insulin sensitivity. And Csiszar et al. showed that sirtuin 1 acts as part of the antioxidant pathway in CR, since disrupting it with small interfering RNA attenuated the antioxidant effects of CR serum. Further research could attempt to determine whether an upregulation of sirtuin 1 is necessary for the insulin-dependent cognitive changes due to CR. If such a shift in sirtuin 1 gene expression were found, it would lend credence to the insulin explanation of the age-related differential effects of CR. But regardless of whether the specific explanation proposed in this paper has merit, the age-dependent effects of CR on memory deserve further study. It has the potential to elucidate a number of currently incomplete pathways, such as insulin resistance, resistance to oxidative stress, and possibly even beta amyloid plaque buildup.
Csiszar A, et al. 2009 Anti-oxidative and anti-inflammatory vasoprotective effects of caloric restriction in aging: role of circulating factors and SIRT1. Pubmed here.
Witte AV, et al. 2009 Caloric restriction improves memory in elderly humans. doi: 10.1073/pnas.0808587106
Hyun DH, et al. 2006 Caloric restriction up-regulates the plasma membrane redox system in brain cells and suppresses oxidative stress during aging. PNAS here.
Redman LM, et al. 2008 Effect of caloric restriction in non-obese humans on physiological, psychological and behavioral outcomes. Pubmed here.