A new study published in Neurobiology of Aging has shown that neither caloric restriction nor intermittent fasting improve late-life cognition in genetically diverse mice, but the effect depends on genetic composition .
Eat less, think better?
Dietary interventions are known to have potential to extend lifespan and delay age-associated diseases, at least in animal models. Caloric restriction and intermittent fasting have become particularly popular among scientists inquiring about possible longevity-promoting mechanisms and longevity enthusiasts who want to experiment with their bodies.
There are some anecdotal reports of how caloric restriction or intermittent fasting regimens make people think clearer after the initial brain fog is overcome. On the other hand, scientific evidence of improved cognition following any of these regimens is conflicting. Moreover, people tend to share success stories and are vulnerable to the placebo effect. It is also possible that dietary restriction could be beneficial for some and detrimental for others.
This study sought to explore if caloric restriction and intermittent fasting improve cognitive function in the Diversity Outbred, a heterogeneous strain of mice that models the genetic diversity of humans. The experiments were conducted on 940 6-month old female mice divided into five groups: freely fed controls, 20% caloric restriction, 40% caloric restriction, 1-day intermittent fasting, and 2-day intermittent fasting.
Eat less, remember less, live more
First, the researchers assessed the working memory of the young (10-month-old) and middle-aged (22-month-old) mice following the diets using a behavioral task, in which the animals are free to explore a Y-shaped maze. Healthy young mice tend to prefer unexplored maze arms and therefore have a higher percentage of “spontaneous alterations.” The researchers did not observe any significant difference in young and old mice due to dietary changes. They hypothesize that because no spatial cues were provided to mice, the task was hippocampus-independent, and therefore might not be sensitive to age-related cognitive decline.
Next, to assess the effect of the diets on memory acquisition, consolidation, and recall, the researchers exposed the 24-month old mice to contextual fear conditioning. The mice were given four foot shock stimulations on day 1 (training), and time spent freezing after each shock was determined. The analysis showed that none of the diets affected the fear acquisition. Moreover, fear memory estimated by the time spent freezing on day 2 (testing, no shocks) revealed that 40% caloric restriction impaired memory recall, while other feeding regimes did not differ from controls.
Importantly, although the dietary restrictions used in this study did not promote late-life cognitive performance, they were effective in extending the lifespan of mice. The researchers showed that more mice following any of the diets survived till the age of 24 months old, compared to the freely fed controls. 40% caloric restriction was the most effective intervention for lifespan extension.
It’s all about genetics
Interestingly, the researchers noticed that the cognitive performance of Diversity Outbred mice varied more than that of genetically homogenous mice. Perhaps not surprisingly, this variance can be explained by the genetic diversity of the mice. In other words, how well a specific mouse on a certain diet performs on cognitive tests depends on its genetic background.
The researchers then identified that a specific region of chromosome 10 containing Slc16a7 gene encoding a lactate and pyruvate transporter (monocarboxylate transporter 2) was responsible for the varied cognitive outcomes in response to the dietary restrictions. Previous research has already shown its involvement in cognitive performance.
Several studies report that caloric restriction (CR) or intermittent fasting (IF) can improve cognition, while others report limited or no cognitive benefits. Here, we compare the effects of 20% CR, 40% CR, 1-day IF, and 2-day IF feeding paradigms to ad libitum controls (AL) on Y-maze working memory and contextual fear memory (CFM) in a large population of Diversity Outbred mice that model the genetic diversity of humans. While CR and IF interventions improve lifespan, we observed no enhancement of working memory or CFM in mice on these feeding paradigms, and report 40% CR to be damaging in the context of long-term memory. Using Quantitative Trait Loci mapping, we identified the gene Slc16a7 to be associated with late-life long-term memory outcomes in mice on lifespan promoting feeding paradigms. Limited utility of dieting and fasting on memory in mice that recapitulate genetic diversity in the human population highlights the need for anti-aging therapeutics that promote cognitive function, with a neuronal monocarboxylate transporter encoded by Slc16a7 highlighted as novel target.
This enlightening study attempts to model how dietary restriction regimes would affect cognitive performance in aging humans. Simply put, it depends on genes. If the results of the study are transferable to humans, it’s possible that the “right” sequence of Slc16a7 and other genes will confer benefits from caloric restriction and/or intermittent fasting, while incompatible individuals would not receive any such benefits. At the same time, none of the regimens described in the study improved cognitive functions in aged mice, with 40% caloric restriction bringing detrimental results despite being the most effective in extending lifespan. It may be that the question of whether someone wants to live longer in a sicker body is not completely pointless after all.
 Ouellette, A. R. et al. Life-long Dietary Restrictions have Negligible or Damaging Effects on Late-life Cognitive Performance: A Key Role for Genetics in Outcomes. bioRxiv 2022.04.09.487742 (2022) doi:10.1101/2022.04.09.487742.