In addition, prospective studies on humans have shown promising effects. One study showed that alternate-day fasting (consuming 25% of energy needs on the fast day and normal food intake on the following day) was effective in decreasing body weight as well as cholesterol levels. In a 10 week trial (2 week control period, 4 week alternate-day fasting period with controlled food intake, and 4 week alternate-day fasting period with self-selected food intake) involving 16 adults, those who underwent the paradigm lost an average of 0.68kg each week over the fasting periods, and a total of 5.8 kg on average over all 8 weeks of the fasting periods. Total cholesterol, LDL cholesterol, and triacylglycerol concentrations decreased as well (by 21, 25 and 32, respectively), without concurrent decreases in HDL cholesterol. Furthermore, average systolic blood pressure decreased a significant amount from 124 mmHg to 116 mmHg at the end of the fasting periods.1
Glucose tolerance changes in response alternate day fasting has been studied. In a study involving 11 non-obese subjects between BMI 20 to 30 kg/m^2, it was fond that after 3 weeks of alternate day fasting, women exhibited slightly impaired glucose response to meals while men did not exhibit significant changes. Men exhibited reductions in insulin response, however. On the other hand, there were no significant changes in expression of genes that are known to play a role in oxidative stress and mitochondrial biogenesis. However, there was a positive trend of increase in CPT1 expression in response to the alternate day fasting. In this study, a gene for longevity, SIRT1, was found to have increased expression.2
While there is skepticism around whether or not intermittent fasting may influence oxidative stress, studies have shown that it is fairly tolerable to humans. One study showed that intermittent fasting (for two separate 3-week periods) did not change gene expression in genes and other biomarkers related to oxidative stress. The study also found that intermittent fasting led to decreased plasma insulin levels.3
A study on 8 healthy men, showed that intermittent fasting every second day (for 20 h at a time, for a total period of 15 days) was effective in increasing insulin-mediated whole body glucose uptake rates by a significant amount (increased from 6.3 ± 0.6 to 7.3 ± 0.3 mg/kg/min) as well as in increasing insulin-induced inhibition of adipose tissue lipolysis. The plasma biomarkers adiponectin (a protein involved in regulating glucose levels and mediating fatty acid breakdown) and leptin (a protein that regulates/inhibits hunger) was studied as well, and it was shown that adiponectin levels were increased compared to basal levels and that leptin levels were decreased.4
There are significant increases in levels of adiponectin after fasting (measured on days 6,10,and 14) as well as significant decreases in leptin after fasting.
A 3-month long human trial in 20 human subjects found that fasting resulted in several favorable changes in biological markers associated with improved metabolism. In this trial, the participants on an intermittent fasting diet went through a 3-month long diet that was characterized by a "fasting-mimicking diet" (FMD) 5-day period at the beginning of each month, followed by a normal diet on other days of the month. The period was characterized by 1 day of consumption of 1000 kcal (10% protein, 56% fat, 34% carbohydrate) followed by 4 days of consumption of 725 kcal (9% protein, 44% fat, 47% carbohydrate). Participants in the control group underwent a normal diet for the entire 3-month period. At the end of the time period for the trial, it was found that that those individuals undergoing fasting exhibited lower blood levels of glucose, IGF-1 (insulin-like growth factor), and C-reactive protein. Furtherore, these individuals exhibited increased levels of ketone bodies (indicating increased ketosis), increased levels of IGFBP-1 (insulin-like growth factor binding protein -- where a higher level correlates with stronger insulin sensitivity) and lower body weight and trunk fat. All of these changes are consistent with improved metabolic function, and supported the results in studies in yeast and mice.5
In a 3-month long human trial, it was found that fasting led to lower blood levels of glucose, IGF-1 and C-reactive protein, and increased levels of IGFBP-1 and ketones. Further, participants undergoing fasting exhibited decreases in body weight and trunk fat.
In humans and most mammals, the liver stores energy in the form of glycogen, which is the first source of energy when metabolic reserves are required. In general, 12-24 hours of fasting can deplete these stores of glycogen, and reduce blood glucose by 20% or more. Once these reserves are extinguished, the body switches to utilizing other sources of energy such as fat-derived ketone bodies and free fatty acids.
Prolonged fasting is fasting for greater than 48 - 120 hours, and intermittent fasting is repeating this cycle on a regular basis. The effects of fasting for longer than 24 hours are much greater, in part because of the switch from glycogen (sugar) based metabolism to fat and ketone-body based metabolism.6
In a 2007 meta-analysis of caloric restriction and alternate-day fasting, animal studies of alternate day fasting demonstrate reduced diabetes incidence, and reduced fating glucose and insulin concentrations. . In terms of cardiovascular disease risk, animal alternate day fasting data show lower total cholesterol and triacylglycerol concentrations, a lower heart rate, improved cardiac response to myocardial infarction, and lower blood pressure.7Reduction of IGF-1 receptor levels and lifespan have been also been seen in mice.
Knock out of one one copy of Igf-1 receptor (Igfr+/-) results in female mice living 33% longer than their wildtype counterparts (Igf1r(+/+), and male mice living 15.9% longer than their wild type counterparts.
In addition, there is a growing interest in understanding metabolic state, including situations of intermittent fasting, with systems biology approaches. Researchers have used techniques such as network-based analysis to identify signatures of genes or epigenetic markers (such as transcription factors) that influence the implications of nutrition on aging in various subpopulations.8One study was able to successfully identify transcriptomic signatures from obese mice (IL-1RI -/-) that were subjected to high-fat diets. Adipose tissue was taken from the mice and a protein-protein interaction network involving proteins for inflammation was analyzed with network analysis algorithms. There was evidence of differential expression of biomarkers that are related to adipogenesis in these mice, including in genes involved in lipid metabolism, the TCA cycle, and interleukin-1 (IL-1, known to play a role in adipogenesis.)9
Varady, K. A., Bhutani, S., Church, E. C., & Klempel, M. C. (2009). Short-term modified alternate-day fasting: a novel dietary strategy for weight loss and cardioprotection in obese adults. The American journal of clinical nutrition, 90(5), 1138-1143.
Heilbronn, L. K., Civitarese, A. E., Bogacka, I., Smith, S. R., Hulver, M., & Ravussin, E. (2005). Glucose tolerance and skeletal muscle gene expression in response to alternate day fasting. Obesity research, 13(3), 574-581.
Wegman, M.P., Guo, M.H., Bennion, D.M., Shankar, M.N., Chrzanowski, S.M., Goldberg, L.A., ... & Brantly, M.L. (2015). Practicality of Intermittent Fasting in Humans and its Effect on Oxidative Stress and Genes Related to Aging and Metabolism. Rejuvenation research.
Halberg, N., Henriksen, M., Söderhamn, N., Stallknecht, B., Ploug, T., Schjerling, P., & Dela, F. (2005). Effect of intermittent fasting and refeeding on insulin action in healthy men. Journal of Applied Physiology, 99(6), 2128-2136.
Brandhorst, S., Choi, I. Y., Wei, M., Cheng, C. W., Sedrakyan, S., Navarrete, G., ... & Di Biase, S. (2015). A periodic diet that mimics fasting promotes multi-system regeneration, enhanced cognitive performance, and healthspan. Cell metabolism, 22(1), 86-99.
Cheng, C. W., Adams, G. B., Perin, L., Wei, M., Zhou, X., Lam, B. S., . . . Longo, V. D. (2014). Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression. Cell Stem Cell, 14(6), 810-823. doi:10.1016/j.stem.2014.04.014
Lacroix, S., Lauria, M., Scott-Boyer, M. P., Marchetti, L., Priami, C., & Caberlotto, L. (2015). Systems biology approaches to study the molecular effects of caloric restriction and polyphenols on aging processes. Genes & nutrition, 10(6), 1-10.
Morine, M. J., Toomey, S., McGillicuddy, F. C., Reynolds, C. M., Power, K. A., Browne, J. A., ... & Roche, H. M. (2013). Network analysis of adipose tissue gene expression highlights altered metabolic and regulatory transcriptomic activity in high-fat-diet-fed IL-1RI knockout mice. The Journal of nutritional biochemistry, 24(5), 788-795.
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