March 29th, 2018
 

Research on intermittent fasting and caloric restriction dieting has demonstrated beneficial effects on blood pressure, glucose metabolism, body fat reduction, inflammation, cognitive function, and length of life in rats (1, 2, 3, 7, 8, 9, 10, 11, 12, 13). 

Proposed mechanisms explaining the advantageous effects of fasting include an increased expression of brain-derived neurotrophic factor (BDNF) (3). In rats, studies have shown that intermittent fasting increases BDNF which aids the brain in the growth, development, and protection of neurons during times of stress, which can help them survive longer. When mammals are fasting, their livers run out of glucose and glycogen, forcing the body to metabolize fat which releases ketones into the blood to be used as energy. When these ketones are utilized by the brain, BDNF levels are increased along with stress adaptability. Fasting has resulted in the increase of adiponectin levels (2). Adiponectin increases insulin sensitivity and has a cardioprotective effect, with low levels being associated with cardiovascular disease and obesity. The ghrelin hormone, which is increased during hunger, has been shown to improve the amount and functionality of T-cells, which are critical to eliciting proper immune responses (14). Ghrelin also has been shown to increase insulin sensitivity, ensuring proper glucose metabolism. The nervous system could benefit from fasting because studies have shown that fasting increases protein chaperone levels which ensure that proteins are functioning properly, the antioxidant defense mechanisms against free radicals are strengthened, and inflammatory cytokines are decreased (3). Fasting also reduced cholesterol and triglyceride levels, which pose a cardiovascular risk. Significant decreases in circulating insulin, glucose, and IGF-1 have been observed. These are associated with greater risks of cancer and aging (3). Caloric restriction and intermittent fasting have increased the expression of peroxisome proliferator-activated receptor (PPAR) coactivator 1 (PGC-1) in rats. PGC-1 activates PPAR, which helps cells to adapt and survive during times of stress. Mice with activated PPAR receptors have shown more cellular resilience and higher survival when exposed to stressors (15, 16). PPAR activation seems to be associated with decreased levels of lipid peroxide, which is associated with aging and cellular damage (17).  

In humans, one study consisted of ten obese patients with asthma and examined the effects of a diet that significantly restricted caloric intake. The study showed significant improvements in asthma symptoms, quality of life, cholesterol and triglyceride levels, and decreased levels of inflammatory and oxidative stress markers (18). Another study of one hundred and seven obese women at risk for breast cancer showed an overall reduction in blood pressure, cholesterol, triglycerides, and inflammatory markers (19). A 1997 study including twenty five women and implementing caloric restriction measured cognitive abilities and showed an increased verbal memory performance by 24% with a slowed simple reaction time (20). Fifty elderly patients were included in a study which employed caloric restriction, this study also showed significantly increased verbal memory performances (6). Fasting followed by a vegetarian diet has lead to significant improvements in pain and inflammation in patients with rheumatoid arthritis (21). Two studies, one consisting of sixty eight patients and the other of one hundred and seventy four, showed impressive blood pressure lowering effects from an intense water only diet (24, 25). Thirty two obese subjects were given an alternate day fasting diet for eight weeks in a 2013 study, and showed weight loss and reductions in cholesterol levels. One hundred and seven obese women were included in one study and given a calorie restricted diet for six months. The results showed decreases in blood pressure, inflammatory markers such as C-reactive protein, and cholesterol (19).

Larger studies in humans are needed to determine exactly which type of fasting is best, along with the long term effects in humans. Some studies are currently being conducted (22, 23). It is likely that fasting for 10-16 hours, for two nonconsecutive days per week, will have beneficial health effects. Benefits are more likely if the person dose not over eat when they begin eating again and if they also maintain a healthy diet and lifestyle. On fasting days, eating less than five hundred total calories is likely to provide the most benefit. Due to a lack of research, patients who are elderly, very young, or underweight should not fast unless their doctor has approved.

By Evan Redmond, Pharm.D.

References:

1. Mattson, Mark P. “Beneficial Effects of Intermittent Fasting and Caloric Restriction on the Cardiovascular and Cerebrovascular Systems.” Journal of Nutritional Biochemistry. 2005; vol. 16: pp. 129–137. pdfs.semanticscholar.org/23da/14a61e0bfa9de0e54dbf9155c0fd45122c56.pdf.

2. Ruiqian Wan, Ismayal Ahmet, Martin Brown. “Cardioprotective effect of intermittent fasting is associated with an elevation of adiponectin levels in rats.” Journal of Nutritional Biochemistry. May 2010; Issue 5: pp 413-417. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2854256/.

3. Martin B, Mattson MP, Maudsley S. “Caloric restriction and intermittent fasting: Two potential diets for successful brain aging.” Aging Research Reviews. 2006; 5(3) :pp 332-353. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2622429/.

4. Raeini-Sarax M, Vanstone CA, Papamandjaris AA, Wykes LJ, Jones PJ. “Comparison of the effect of dietary fat restriction with that of energy restriction on human lipid metabolism.” The American Journal of Clinical Nutrition. 2001;73(2): pp 262-7. https://www.ncbi.nlm.nih.gov/pubmed/11157322.

5. Meckling KA, Gauthier M, Grubb R, Sanford J. “Effects of a hypocaloric, low-carbohydrate diet on weight loss, blood lipids, blood pressure, glucose tolerance, and body composition in free-living overweight women.” Canadian Journal of Physiology and Pharmacology. 2002; 80(11): pp 1095-105. https://www.ncbi.nlm.nih.gov/pubmed/12489929.

6. Witte AV, Fokker M, Gellner R, Knecht S, Floel A.“Caloric restriction improves memory in elderly humans”. Proceedings of the National Academy of Sciences of the U.S.A. 2009;106(4): pp 1255-60. https://www.ncbi.nlm.nih.gov/pubmed/19171901.

7. Singh R, Lakhanpal D, Kumar S, Sharma S, Kataria H, Kaur M, Kaur G. “Late-onset intermittent fasting dietary restriction as a potential intervention to retard age-associated brain function impairments in male rats.” Age (Dordr). 2012; 34(4): pp 917-33. https://www.ncbi.nlm.nih.gov/pubmed/21861096.

8. Fontan-Lozano A, Saez-Cassanelli JL, Inda MC. “Caloric restriction increases learning consolidation and facilitates synaptic plasticity through mechanisms dependent on NR2B subunits of the NMDA receptor.” The Journal of Neuroscience. 2007 Sep 19; 27(38): pp 10185-95. http://www.jneurosci.org/content/27/38/10185.

9. Carlson AJ, Hoelzel F. “Apparent prolongation of the life span of rats by intermittent fasting.” The Journal of Nutrition. 1946 Mar; 31: pp 363-75. https://www.ncbi.nlm.nih.gov/pubmed/21021020.

10. Kendrick DC. ”The effects of infantile stimulation and intermittent fasting and feeding on life span in the black-hooded rat.” Developmental Psychobiology.1973 May; 6(3): pp 225-34. https://onlinelibrary.wiley.com/doi/abs/10.1002/dev.420060307.

11. Halagappa VK, Guo Z, Pearson M, Matsuoka Y, Cutler RG, Laferla FM, Mattson MP. ”Intermittent fasting and caloric restriction ameliorate age-related behavioral deficits in the triple-transgenic mouse model of Alzheimer's disease.” Neurobiology of Disease. 2007 Apr; 26(1): pp 212-20. https://www.ncbi.nlm.nih.gov/pubmed/17306982.

12. Castella L, Froio T, Maina M. “Alternate-day fasting protects the rat heart against age-induced inflammation and fibrosis by inhibiting oxidative damage and NF-kB activation.” Free Radical Biology & Medicine. 2010 Jan 1; 48(1): pp 47-54. https://www.ncbi.nlm.nih.gov/pubmed/19818847.

13. Wan R, Camandola S, Mattson MP.“Intermittent fasting and dietary supplementation with 2-deoxy-D-glucose improve functional and metabolic cardiovascular risk factors in rats.” FASEB J. 2003 Jun; 17(9): pp 1133-4. https://www.ncbi.nlm.nih.gov/pubmed/12709404.

14. Longo VD, Mattson MP. “Fasting: Molecular Mechanisms and Clinical Applications.” Cell Metabolism. 2014; 19(2): pp 181-192. https://www.ncbi.nlm.nih.gov/pubmed/24440038.

15. Anderson SP, Yoon L, Richard EB. “Delayed liver regeneration in peroxisome proliferator-activated receptor-alpha-null mice.” Hepatology. 2002 Sep; 36(3): pp 544-54. https://www.ncbi.nlm.nih.gov/pubmed/12198646.

16. Wheeler MD, Smutney OM, Check JF. ”Impaired Ras membrane association and activation in PPARalpha knockout mice after partial hepatectomy.” American Journal of Physiology. Gastrointestinal and Liver Physiology. 2003 Feb; 284(2): pp 302-12. https://www.ncbi.nlm.nih.gov/pubmed/12388208.

17. Poynter MA, Daynes RA, et al.“Peroxisome proliferator-activated receptor alpha activation modulates cellular redox status, represses nuclear factor-kappaB signaling, and reduces inflammatory cytokine production in aging.” The Journal of Biological Chemistry. 1998 Dec 4; 273(49):32833-41. https://www.ncbi.nlm.nih.gov/pubmed/9830030.

18. Johnson JN, Summer W, Cutler RG, Martin B, et al. “Alternate day calorie restriction improves clinical findings and reduces markers of oxidative stress and inflammation in overweight adults with moderate asthma.” Free Radiccal Biology and Medicine. 2007 Mar 1; 42(5): pp 665-74. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1859864/.

19. Harvie MN, Pegington M, Mattson MP, et al.“The effects of intermittent or continuous energy restriction on weight loss and metabolic disease risk markers: a randomized trial in young overweight women.” International Journal of Obesity. 2011 May; 35(5): pp 714-27. https://www.ncbi.nlm.nih.gov/pubmed/20921964.

20. Kretsch MJ, Green MW, et al. “Cognitive effects of a long-term weight reducing diet.” International Journal of Obesity and Related Metabolic Disorders. 1997 Jan; 21(1): pp 14-21. https://www.ncbi.nlm.nih.gov/pubmed/9023595.

21. Muller H, de Toledo FW, Resch KL.“Fasting followed by vegetarian diet in patients with rheumatoid arthritis: a systematic review.“ Scandinavian Journal of Rheumatology. 2001; 30(1): pp 1-10. https://www.ncbi.nlm.nih.gov/pubmed/11252685.

22. https://www.nia.nih.gov/alzheimers/clinical-trials/intermittent-calorie-restriction-insulin-resistance-and-brain-function.

23. https://www.nia.nih.gov/alzheimers/clinical-trials/dietary-ketosis-memory-loss-and-mci.

24. Goldhammer AC, Lisle DJ, Sultana P, et al."Medically supervised water-only fasting in the treatment of borderline hypertension." Journal of Alternative and Complementary Medicine. 2002 Oct; 8(5): pp 643-50. https://www.ncbi.nlm.nih.gov/pubmed/12470446/.

25. Goldhammer AC, Lisle DJ, et al."Medically supervised water-only fasting in the treatment of hypertension." Journal of Manipulative and Physiological Therapeutics. 2001 Jun; 24(5): pp 335-9. https://www.ncbi.nlm.nih.gov/pubmed/11416824/.