CR as a therapeutic diet is not a temporary weight loss method, but rather a long-term way to maintain lifelong good health. It involves reducing average daily caloric intake to below what is usual, but still covering basic nutritional needs1. Studies often point to a reduction of about 30% of typical caloric intake (range 10-40%) as having beneficial effects on the body 2,3, including improved immune function4 and memory 5.

     Among other benefits, CR has been found to be neuroprotective6, due likely to improved cellular function (particularly in the energy-generating mitochondria of the cell) limiting oxidative damage, as well as regulation of gene expression, resulting in decreased activity of damaging compounds with increased levels of neuroprotective factors and activation of adaptive cellular stress responses (called “hormesis”)7,8. In MS patients specifically, other mechanisms through which CR exerts benefits include improved immune cell subsets and metabolic markers 9.

    In a demyelination animal model of MS, a 33% CR promoted remyelination and induced a significant increase in motor coordination and balance performance compared to controls10. These results were repeated in another study in which a portion of calorie-containing food was replaced with an indigestible (non-caloric) plant fiber11.

     In a human study with RRMS patients, a 22% CR was associated with significant improvements in emotional well-being/depression scores relative to control12. A later clinical study reducing calorie intake to approximately 25% of the usual (to 500 or less) on two non-consecutive days per week demonstrated a significant reduction in the neuroinflammation and brain shrinkage associated with MS13.

    Overall, though therapeutic CR has been performed successfully in some human studies14,15, it is considered to be difficult to sustain, something to which many people following weight loss diets can attest. For this reason, alternative interventions that mimic protective effects of CR are being sought3. One such intervention is a fasting mimicking diet (a type of intermittent fasting), which was associated with benefits similar to CR in a human study12.

     While the nature of a CR diet does not dictate the macronutrient composition or which foods to be included or avoided, it has been recommended to favor high-quality choices in order to meet nutritional needs6,13.

References

1. Aging. NIo. Calorie Restriction and Fasting Diets: What Do We Know? Accessed 08 Feb 2022. https://www.nia.nih.gov/news/calorie-restriction-and-fasting-diets-what-do-we-know#:~:text=Calorie%20restriction%20means%20reducing%20average,day%2C%20week%2C%20or%20month.

2. Anderson RM, Shanmuganayagam D, Weindruch R. Caloric restriction and aging: studies in mice and monkeys. Toxicol Pathol. Jan 2009;37(1):47-51. doi:10.1177/0192623308329476

3. Lane MA, Mattison J, Ingram DK, Roth GS. Caloric restriction and aging in primates: Relevance to humans and possible CR mimetics. Microsc Res Tech. Nov 15 2002;59(4):335-8. doi:10.1002/jemt.10214

4. Nikolich-Zugich J, Messaoudi I. Mice and flies and monkeys too: caloric restriction rejuvenates the aging immune system of non-human primates. Exp Gerontol. Nov 2005;40(11):884-93. doi:10.1016/j.exger.2005.06.007

5. Witte AV, Fobker M, Gellner R, Knecht S, Floel A. Caloric restriction improves memory in elderly humans. Proc Natl Acad Sci U S A. Jan 27 2009;106(4):1255-60. doi:10.1073/pnas.0808587106

6. Oudmaijer CAJ, Komninos DSJ, Hoeijmakers JHJ, JNM IJ, Vermeij WP. Clinical implications of nutritional interventions reducing calories, a systematic scoping review. Clin Nutr ESPEN. Oct 2024;63:427-439. doi:10.1016/j.clnesp.2024.06.046

7. Calabrese EJ, Bachmann KA, Bailer AJ, et al. Biological stress response terminology: Integrating the concepts of adaptive response and preconditioning stress within a hormetic dose-response framework. Toxicol Appl Pharmacol. Jul 1 2007;222(1):122-8. doi:10.1016/j.taap.2007.02.015

8. Mattson MP. Hormesis defined. Ageing Res Rev. Jan 2008;7(1):1-7. doi:10.1016/j.arr.2007.08.007

9. Fitzgerald KC, Bhargava P, Smith MD, et al. Intermittent calorie restriction alters T cell subsets and metabolic markers in people with multiple sclerosis. EBioMedicine. Aug 2022;82:104124. doi:10.1016/j.ebiom.2022.104124

10. Mojaverrostami S, Pasbakhsh P, Madadi S, et al. Calorie restriction promotes remyelination in a Cuprizone-Induced demyelination mouse model of multiple sclerosis. Metab Brain Dis. Oct 2020;35(7):1211-1224. doi:10.1007/s11011-020-00597-0

11. Zarini D, Pasbakhsh P, Nekoonam S, et al. Protective Features of Calorie Restriction on Cuprizone-induced Demyelination via Modulating Microglial Phenotype. J Chem Neuroanat. Oct 2021;116:102013. doi:10.1016/j.jchemneu.2021.102013

12. Fitzgerald KC, Vizthum D, Henry-Barron B, et al. Effect of intermittent vs. daily calorie restriction on changes in weight and patient-reported outcomes in people with multiple sclerosis. Mult Scler Relat Disord. Jul 2018;23:33-39. doi:10.1016/j.msard.2018.05.002

13. Rahmani F, Ghezzi L, Tosti V, et al. Twelve Weeks of Intermittent Caloric Restriction Diet Mitigates Neuroinflammation in Midlife Individuals with Multiple Sclerosis: A Pilot Study with Implications for Prevention of Alzheimer’s Disease. J Alzheimers Dis. 2023;93(1):263-273. doi:10.3233/JAD-221007

14. Maalouf M, Rho JM, Mattson MP. The neuroprotective properties of calorie restriction, the ketogenic diet, and ketone bodies. Brain Res Rev. Mar 2009;59(2):293-315. doi:10.1016/j.brainresrev.2008.09.002

15. Zhang B, Huang R, Xu S, et al. Dietary energy restriction in neurological diseases: what’s new? Eur J Nutr. Mar 2023;62(2):573-588. doi:10.1007/s00394-022-03036-1