In a recent Nature Communications paper, the researchers investigated changes in weight, metabolism, and microbiome that resulted from periodic restricted feeding in non-human primates [1].
Continuous vs. time-restricted caloric restriction
Caloric restriction, which limits the amount of calories an organism consumes, is a widely known lifespan-extending intervention in laboratory animals [2]. How caloric restriction is conducted varies by such factors as the exact number of calories, dietary content, timing, and the length of treatment.
Typical caloric restrictions require restricting caloric intake for a long period of time, but variations to that protocol are being studied. One approach is time-restricted eating, in which the animal fasts for some period of the day and, after this, is allowed to eat without restrictions. This can also be implemented over time, with several days of caloric restriction followed by several days of unrestricted eating. The authors of this paper refer to this scheme as periodic restricted feeding.
Fewer calories, lower body weight
Periodic restricted feeding has been shown to be successful in rodents for “regulating healthy metabolism, body weight, and healthspan” [3]. The authors of this paper tested it in rhesus macaques (Macaca mulatta), non-human primates that are commonly used in experiments. The authors restricted the caloric intake of the animals for four days, with a 50% restriction on the first day and a 70% restriction on the following three days. Following the caloric restriction period, animals were allowed to eat without restrictions for ten days. Such a pattern was repeated for six cycles.
The experiment was rather small, as it contained only 12 male and 11 female adult rhesus monkeys. The group was divided into two groups: a control with constant food access and a periodically restricted feeding group.
The first observation described in the paper is the impact of periodic restricted feeding on body mass. The animals whose caloric intake was restricted lost weight. This was true whether animals were compared to their original baselines (the mean body mass loss was 5%) or to animals who had an unrestricted diet.
Calorically restricted animals consumed roughly 10% to 30% less food compared to controls. The amount of reduced food intake was not directly correlated with the loss of body weight. The researchers are curious about the missing pieces in this puzzle, suggesting that future measurements of energy expenditure, metabolic rate, and activity might shed more insight on the relationship between caloric restriction and body weight.
Metabolome-microbiome alterations
In the next step, the researchers quantified 866 metabolites from blood serum at different time points. They have observed transient changes to the metabolome resulting from periodic restricted feeding. The biggest shifts were observed on day four of caloric restriction in both cycle three and cycle six. However, following refeeding, these changes were reverted almost back to baseline. A closer look into the exact metabolites that changed revealed 56 up- and down-modulated metabolites, mostly in different lipid classes, suggesting the activation of pathways that utilize lipids.
Was the change permanent? Previously done murine research reported persistent metabolic changes following similar cyclical caloric restriction [3]. However, in this study, the researchers observed sex-dependent differences. While in males, metabolic signatures reset to baseline at the end of the study, in females, they overcorrected.
The researchers noted consistency between sex-specific differences in metabolic signatures and long-term body weight changes. Females were observed to quickly regain the weight lost during caloric restriction treatment. In males, on the other hand, weight loss was sustained during the three-year follow-up period. Based on those results, the researchers speculated that in females, weight gain might be correlated to the metabolic signature overcorrection. However, further research is necessary to confirm that.
Continuous caloric restriction is also known to result in changes in the microbiome [4]. The authors of this paper tested if periodic restricted feeding will also cause permanent changes in primates. α-diversity is a measurement of the number and amount of different types of gut bacteria, and this research indicated trends towards ”increased α-diversity during peak diet after three” cycles of food restriction. This is a positive change, as previous research generally observed an association between increased gut diversity and better health [5]. The data suggested that the response was increasing with each cycle.
The researchers also investigated changes in specific groups of bacteria. They observed an increase in the levels of one type that was previously found to decrease in obesity in humans [6]. On the other hand, bacteria that are increased in obesity and type 2 diabetes [7] were reduced following the restricted feeding in this experiment. The researchers also speculate that the changes in microbes influenced the changes in the levels of some of the metabolites in the blood serum.
The gut is also known to interact with the immune system. However, the authors of this study reported that animals that experienced periodic restricted feeding “presented a more stable blood profile compared to” controls. Periodic restricted feeding also didn’t seem to impact the animals’ inflammatory status. They speculate that it might be due to the cyclical refeeding periods that allowed the immune system to retain its functions.
Better for humans?
Strict, continuous dietary restriction is challenging for humans to implement. The authors believe that implementing such a cyclical regime might be easier to implement and sustain and that it still provides many benefits. They believe the data they have shown is promising. However, further characterization with varied diets, levels of restriction, and longer durations is necessary.
“In summary, we found that short-term, consecutive PRF cycles result in a significant loss of body weight and fat percentage in adult rhesus monkeys. This was accompanied by complimentary changes to the gut microbiome and the metabolic profile, with stable hematopoiesis and without discernable negative side effects.”
Literature
[1] Yanai, H., Park, B., Koh, H., Jang, H. J., Vaughan, K. L., Tanaka-Yano, M., Aon, M., Blanton, M., Messaoudi, I., Diaz-Ruiz, A., Mattison, J. A., & Beerman, I. (2024). Short-term periodic restricted feeding elicits metabolome-microbiome signatures with sex dimorphic persistence in primate intervention. Nature communications, 15(1), 1088.
[2] Taormina, G., & Mirisola, M. G. (2014). Calorie restriction in mammals and simple model organisms. BioMed research international, 2014, 308690.
[3] Diaz-Ruiz, A., Rhinesmith, T., Pomatto-Watson, L. C. D., Price, N. L., Eshaghi, F., Ehrlich, M. R., Moats, J. M., Carpenter, M., Rudderow, A., Brandhorst, S., Mattison, J. A., Aon, M. A., Bernier, M., Longo, V. D., & de Cabo, R. (2021). Diet composition influences the metabolic benefits of short cycles of very low caloric intake. Nature communications, 12(1), 6463.
[4] von Schwartzenberg, R. J., Bisanz, J. E., Lyalina, S., Spanogiannopoulos, P., Ang, Q. Y., Cai, J., Dickmann, S., Friedrich, M., Liu, S. Y., Collins, S. L., Ingebrigtsen, D., Miller, S., Turnbaugh, J. A., Patterson, A. D., Pollard, K. S., Mai, K., Spranger, J., & Turnbaugh, P. J. (2021). Caloric restriction disrupts the microbiota and colonization resistance. Nature, 595(7866), 272–277.
[5] Ghosh, T. S., Shanahan, F., & O’Toole, P. W. (2022). The gut microbiome as a modulator of healthy ageing. Nature reviews. Gastroenterology & hepatology, 19(9), 565–584.
[6] Clarke, S. F., Murphy, E. F., Nilaweera, K., Ross, P. R., Shanahan, F., O’Toole, P. W., & Cotter, P. D. (2012). The gut microbiota and its relationship to diet and obesity: new insights. Gut microbes, 3(3), 186–202.
[7] Castaner, O., Goday, A., Park, Y. M., Lee, S. H., Magkos, F., Shiow, S. T. E., & Schröder, H. (2018). The Gut Microbiome Profile in Obesity: A Systematic Review. International journal of endocrinology, 2018, 4095789.
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