Long-term Intermittent Fasting Research Articles

Long-term intermittent fasting induces sex-dependent changes in small intestine from SAMP8 aged mice

Background: Intermittent fasting (IF) is a popular and effective method to decrease body weight. Yet, the effects of IF on aged intestine is unknown. SAMP8 (Senescence Accelerated Mouse-Prone 8) mice are used as a model for studying aging. This study aimed to examine the potential for IF to ameliorate age-associated disturbances in murine jejunum. Methods: Two-month-old male and female SAMP8 mice were randomly assigned to either an IF protocol or an ad-libitum diet (AL) for the 8-month study (n=7-10 group). Fasted mice followed a 24-hour alternate day fasting protocol. At the end of the study mice were euthanized and jejunum stored at −80°C until use for western blot or other assay, and a segment was fixed for histology. Results: IF resulted in significantly less weight gain in both males (22% less, n=7-10, p<0.05) and females (33% less, n=7-8, p<0.05) and response to glucose load (glucose tolerance testing) was comparable in both sexes: area under curve for AL > IF. Interestingly, IF significantly reduced fasting serum glucose levels in males (30% less, n=6, p<0.05), but IF had no effect on fasting serum glucose in females. In jejunum, we assessed: protein expression, health, and morphology. In females, IF led to a 57% decrease in GLUT2 expression (n=5-6, p<0.05) versus AL. GLUT2 moves glucose/galactose and fructose out of the enterocyte into the blood, suggesting restructuring of monosaccharide transport due to IF. IF had no effect on jejunum GLUT5 or SGLT1 expression. Cleaved Caspase-3 expression was decreased by IF in both sexes versus AL. This reduction was greater in females, suggesting a sex-dependent protective role of IF against apoptosis. Moreover, IF induced a significant increase 1.4-fold (n=5=6, p<0.05) in jejunum superoxide dismutase (SOD) activity in both sexes. Jejunum morphology was significantly changed in females only: IF induced both a decrease in villi length (by 21%, n=4/group, p<0.05) and a decrease in wall thickness (by 7%, n=4/group, p<0.05). Conclusions: In both sexes, IF decreased body weight, yet in females resting glucose levels were unchanged by IF. In females, IF reduced monosaccharide absorption out of intestines, yet improved overall intestinal health, increasing antioxidant levels with SOD. These findings collectively highlight the complex effects of IF on cellular processes and demonstrate significant sex-dependent aged intestinal responses. Unraveling the underlying molecular mechanisms driving these sex-dependent IF-induced effects is currently under evaluation. Midwestern-Arizona Alzheimer’s Consortium Grant, Midwestern University Intramural Grant. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effects of intermittent fasting on periodontal inflammation and subgingival microbiota.

Studies on the impact of intermittent fasting on periodontal health are still scarce. Thus, this study evaluated the effects of long-term intermittent fasting on periodontal health and the subgingival microbiota. This pilot study was part of a nonrandomized controlled trial. Overweight/obese participants (n=14) entered an intermittent fasting program, specifically the 5:2 diet, in which they restricted caloric intake to about a quarter of the normal total daily caloric expenditure for two nonconsecutive days/week. Subjects underwent a thorough clinical and laboratory examination, including an assessment of their periodontal condition, at baseline and 6months after starting the diet. Additionally, subgingival microbiota was assessed by 16S rRNA gene sequencing. After 6months of intermittent fasting, weight, body mass index, C-reactive protein, hemoglobin A1c (HbA1c), and the cholesterol profile improved significantly (p<0.05). Moreover, significant reductions were observed in bleeding on probing (p=0.01) and the presence of shallow periodontal pockets after fasting (p<0.001), while no significant change was seen in plaque index (p=0.14). While we did not observe significant changes in α- or β-diversity of the subgingival microbiota related to dietary intervention (p>0.05), significant differences were seen in the abundances of several taxa among individuals exhibiting ≥60% reduction (good responders) in probing pocket depth of 4-5mm compared to those with <60% reduction (bad responders). Intermittent fasting decreased systemic and periodontal inflammation. Although the subgingival microbiota was unaltered by this intervention, apparent taxonomic variability was observed between good and bad responders.

Long-term intermittent fasting improves neurological function by promoting angiogenesis after cerebral ischemia via growth differentiation factor 11 signaling activation.

Intermittent fasting (IF), an alternative to caloric restriction, is a form of time restricted eating. IF conditioning has been suggested to have neuroprotective effects and potential long-term brain health benefits. But the mechanism underlying remains unclear. The present study focused on the cerebral angiogenesis effect of IF on ischemic rats. Using a rat middle cerebral artery occlusion model, we assessed neurological outcomes and various vascular parameters such as microvessel density (MVD), regional cerebral blood flow (rCBF), proliferation of endothelial cells (ECs), and functional vessels in the peri-infarct area. IF conditioning ameliorated the modified neurological severity score and adhesive removal test, increased MVD, and activated growth differentiation factor 11 (GDF11)/activin-like kinase 5 (ALK5) pathways in a time-dependent manner. In addition, long-term IF conditioning stimulated proliferation of ECs, promoted rCBF, and upregulated the total vessel surface area as well as the number of microvessel branch points through GDF11/ALK5 pathways. These data suggest that long-term IF conditioning improves neurological outcomes after cerebral ischemia, and that this positive effect is mediated partly by angiogenesis in the peri-infarct area and improvement of functional perfusion microvessels in part by activating the GDF11/ALK5 signaling pathway.

The Effect of Ramadan Fasting on the Immune System Function

Fasting is one of the most important Islamic acts of worship ordered by the Holy Prophet Muhammad (Peace be upon him), the great Imams, and Muslim philosophers. It has a tremendous effect on various aspects of human beings, including physical and mental health, cholesterol level control, and triglyceride level control. Moreover, it alleviates the dimensions of depression, psychosis, anxiety, obsession, interpersonal sensitivity, phobia, hostility, and paranoid thoughts. One of the most important effects of fasting on the human body is its influence on the immune system function. Significantly, it has been found that inflammatory biomarkers, such as IL-6 and C-reactive protein (CRP), are suppressed considerably by short- and long-term intermittent fasting. In overweight adults, calorie restriction (CR) improves clinical findings for patients with moderate asthma, reduces oxidative and inflammatory stress markers, and minimizes metabolic disease risk markers.

Maternal intermittent fasting in mice disrupts the intestinal barrier leading to metabolic disorder in adult offspring

Maternal nutrition plays a critical role in energy metabolism of offspring. We aim to elucidate the effect of long-term intermittent fasting (IF) before pregnancy on health outcomes of offspring. Here we show long-term IF before pregnancy disrupts intestinal homeostasis of offspring with subsequent disorder of glucose and lipid metabolism. This occurs through the reduction in beneficial microbiota such as Lactobacillus_intestinalis. Our observations further support the concept that intestinal microbiota in offspring is vulnerable to maternal nutrition, and its homeostasis is critical for the integrity of intestinal barrier and metabolic homeostasis.

Dietary Intake Regulates White Adipose Tissues Angiogenesis via Liver Fibroblast Growth Factor 21 in Male Mice

Obesity and related metabolic disorders have become epidemic diseases. Intermittent fasting has been shown to promote adipose tissue angiogenesis and have an anti-obesity feature; however, the mechanisms of how intermittent fasting modulates adipose tissues angiogenesis are poorly understood. We investigated the effect of fasting on vascular endothelial growth factor (VEGF) levels in white adipose tissues (WAT) and the function of fibroblast growth factor 21 (FGF21) in 1-time fasting and long-term intermittent fasting-induced VEGF expression. In the current study, fasting induced a selective and drastic elevation of VEGF levels in WAT, which did not occur in interscapular brown adipose tissue and liver. The fasting-induced Vegfa expression occurred predominantly in mature adipocytes, but not in the stromal vascular fraction in epididymal WAT and inguinal WAT (iWAT). Furthermore, a single bolus of recombinant mouse FGF21 injection increased VEGF levels in WAT. Long-term intermittent fasting for 16 weeks increased WAT angiogenesis, iWAT browning, and improved insulin resistance and inflammation, but the effect was blunted in FGF21 liver-specific knockout mice. In summary, these data suggest that FGF21 is a potent regulator of VEGF levels in WAT. The interorgan FGF21 signaling-induced WAT angiogenesis by VEGF could be a potential new therapeutic target in combination with obesity-related metabolic disorders.

Enhanced weight and fat loss from long-term intermittent fasting in obesity-prone, low-fitness rats

BackgroundIntermittent fasting (IF) strategies have emerged as viable alternatives to traditional calorie-restricted diets. A key predictor of metabolic health and response to diet is cardiometabolic fitness, including intrinsic aerobic capacity. In a contrasting rat model of aerobic capacity—high- and low-capacity runners (HCR, LCR)—we found that the lean and physically active HCR were also more responsive to a standard calorie-restricted diet. Here, we assessed the ability of IF to induce weight loss on a background of high and low aerobic fitness accompanied by different levels of daily physical activity. MethodsFemale HCR and LCR (8 per line) were subjected to IF (alternate-day fasting) for 14 weeks. Outcomes included changes in body weight, fat and lean mass, daily physical activity, and food and water intake. After initial measurements, IF was continued, and measurements were repeated after one year of IF. ResultsAll rats lost weight with IF, and LCR lost significantly more weight than HCR. This difference was primarily due to differential fat loss; loss of lean mass, on the other hand, was similar between HCR and LCR. Total food intake decreased with IF, and LCR showed lower intake than HCR only during the first 5 weeks of IF. Physical activity was suppressed by long-term IF. Physical activity increased on fed days compared to fasted days, and this pattern was more pronounced in HCR. The differential effects of IF in HCR and LCR persisted after one year of IF, with IF preventing the marked weight gain seen in ad libitum fed LCR during this time. ConclusionWeight and fat loss from IF was more pronounced in obesity-prone, low-aerobic capacity LCR, despite the low activity levels seen in these rats. The possibility that aerobic capacity modulates response to IF in human participants remains unexplored.

Dietary Intake Regulates White Adipose Tissues Angiogenesis via Liver Fibroblast Growth Factor 21

Background: Obesity and related metabolic disorders have become epidemic diseases. Intermittent fasting has been shown to promote adipose tissue angiogenesis and have an anti-obesity feature; however, the mechanisms of how intermittent fasting modulates adipose tissues angiogenesis are poorly understood. Methods: We evaluated the effect of short-time and long-term intermittent fasting on FGF21 and VEGF expression in various tissues in C57BL/6 mice. Cell fractional analysis were used to examine the target cells in WAT were involved in fasting induced VEGF expression. Tail vein injection of recombinant FGF21 to C57BL/6 mice were used to examine the direct effect of FGF21 on VEGF expression. Wild-type and liver-specific ablation of fibroblast growth factor 21 (FGF21 LKO) were fed on a high-fat diet ad libitum or intermittent fasting for 16 weeks, and metabolic phenotypes including body weight, insulin resistance, browning and white adipose tissues angiogenesis were monitored. Findings: In the current study, fasting induced a selective and drastic elevation of VEGF levels in WAT which did not occur in interscapular BAT and liver. The fasting-induced Vegfa expression occurred predominantly in mature adipocytes, but not in the stromal vascular fraction. Furthermore, a single bolus of recombinant mouse FGF21injection increased VEGF levels in WAT. Long-term intermittent fasting increased WAT angiogenesis, iWAT browning, and improved insulin resistance and inflammation, but the effect was blunted in FGF21 LKO mice. Interpretation: In summary, these data suggest that FGF21 is a potent regulator of WAT VEGF levels. The interorgan FGF21 signaling induced WAT angiogenesis by VEGF could be a potential new therapeutic target in combination with obesity-related metabolic disorders. Funding Statement: This study was supported by National Key R&D Program of China (Grant 2018YFD0501005), National Natural Science Foundation of China, PR China (Grant 31772616) and the 111 Project (D17015). Declaration of Interests: The authors have no conflict of interest to declare. Ethics Approval Statement: All animal procedures in this study were approved by the Institutional Animal Care and Research Committee of Sichuan Agricultural University (SICAU-2015-033).

Daily, Long-Term Intermittent Fasting for the Prevention of PSA-Recurrence in Patients With Localized Prostate Cancer After Radical Prostatectomy

Daily, Long-Term Intermittent Fasting for the Prevention of PSA-Recurrence in Patients With Localized Prostate Cancer After Radical Prostatectomy

A Novel 14-Day Dietary Deprivation Regimen Preserves Protein Metabolism During Fasting and Accelerates Muscle Recovery after Refeeding Through Constantly Suppressing Myostatin

Background Fasting has demonstrated a robust lifespan extension in yeast and C. elegans. Although long-term total fasting, intermittent fasting or calorie restriction has been evaluated in clinic, there were long-term safety and practical concerns regarding with these regimens. Methods We have applied a special prebiotics-assisted fasting approach for 7~14 days continual dietary deprivation (CDD) in three trials. Our fasting regimen has achieved total of 25/94 individuals who have successfully accomplished 14D's total fasting. At the third trial, a modified paradigm plus daily mineral electrolytes assistance led up to 50% (15/32) success in fulfilling 14D-CDD. Among the results from successfully accomplishment subjects, one-way ANOVA with repeated measure on 5 treatments within individual has been compared with each own control. Findings Bioelectrical and biochemical results indicated significant reducing in fat mass (lipid) during fasting, while lean mass (protein) remained stable and found more accelerated recovery after refeeding. During 7~9thD CDD, we observed a significant slowing down in basal metabolism rate (BMR 100U/L, refeeding for more than 3 months remained lowered CK level. Fasting 14D also found significant suppression in myostatin, and it remained lower concentration even after 3 months' refeeding. Ultrasonic image confirmed unchanged muscle comparing with adipose during and after 14D fasting. Interpretation Our results indicated that initial fasting (1~7D) induced catabolism in all tissues. As the fasting continues, a preserved muscle mechanism has been established with reducing in BMR, myostatin and CK which might indicate an induction of anabolism through establishing ketone body metabolism. The beneficial evidence from current regimen indicated that repeated application of 14D-CDD every 6 months may supply practical health improvement strategy in facilitating disease treatments. Funding National Basic Research Project of China Declaration of Interest: The other authors declare no competing interests. Ethical Approval: The approval of the study protocol by the University of Henan Human Research Protection Program was under the guidance of China Association for Ethical Studies. The protocol was also recorded in Medical Ethics Committee of Henan Medical Association of Henan Province, and the entire clinical study was under the supervision of ethic board of The First Affiliated Hospital of Henan University.

Abstract 13888: Long-term Intermittent Fasting Treatment Improves Cardiac Function and Inotropic Reserve by Restoration of Cardiac Beta-adrenergic Signaling in an Experimental Model of Chronic Heart Failure

Introduction and Hypothesis: Restricted diets are effective interventions to enhance cardiovascular function and metabolic profile and are known to improve life spam. IF (Intemittent fasting) dietary regimen has a cardioprotective effect in a rat model of myocardial infarction (MI) when diet is started before MI induction. In heart failure (HF), upregulation of G protein-coupled receptor kinase 2 (GRK2) contributes to dysfunctional beta-adrenergic receptor (βAR) signaling and to decrease cardiac inotropic reserve. Moreover, it has been shown that caloric restriction has positive effects on the development of left ventricular hypertrophy and improves ischemic tolerance. Hence, we will test whether a long-term restricted diet, started late after MI, is beneficial in HF and how it could affect cardiac adrenergic signaling. Methods: forty rats were randomly assigned to MI or sham operation. Four weeks later, a time point when post-ischemic HF was established, HF and sham rats were further randomized to a one year IF dietary restriction or ad libitum diet. Thus, our final animal population consisted in 4 groups: Sham normal diet, Sham IF diet, HF normal diet and HF IF diet. Results: One year of IF diet induced a robust decrease in body weight. In HF groups, restricted diet resulted in improved cardiac systolic function and reduced left ventricle end diastolic diameter compared to HF rats fed with normal diet, as measured by echocardiography at the end of the study period. No differences in cardiac function and dimension were observed between sham groups treated with different diets. Consistently, invasive hemodynamic showed that both LV contractility and relaxation in response to βAR stimulation were significantly increased in IF HF rats compared to HF normal diet animals. IF diet resulted in improved cardiac βAR density and adenylyl cyclase activity in HF rats when compared to HF rats treated with standard diet. Restoration of βAR signaling was associated to a dramatic reduction in cardiac GRK2 protein levels. Conclusions: We have demonstrated for the first time that IF, started when HF is already established, ameliorates cardiac function and inotropic reserve in an experimental model of HF. At the molecular level, IF diet significantly improves βAR signaling in HF.