BACKGROUND:Appendicitis is an acute condition of the abdomen that is treated with surgical intervention. Conservative treatment of appendicitis currently involves intravenous antibiotics. While conservative care is a useful tool in apprehensive patients, in conditions such as appendicitis, delays in proper treatment can be life threatening. In spite of this, some patients will still refuse surgical and pharmacologic intervention, which can significantly limit the physician's therapeutic options.

SUBJECT:Sonographic evidence is presented of appendicitis in a patient who strongly desired to avoid pharmacologic or surgical intervention.

RESULTS:The patient underwent a medically supervised water-only fast followed by a plant-based, low-fat, low-sodium diet and achieved a significant reduction and eventual elimination of symptoms.

CONCLUSIONS:This case demonstrates the need for further research on the effects of medically supervised water-only fasting and careful refeeding in cases of uncomplicated appendicitis.

As part of a population-based approach to combating obesity, the American Heart Association has published specific dietary guidelines for the management of obesity and cardiovascular disease prevention. These guidelines give a primary view of healthy dietary changes and goals which may reduce cardiovascular risk. The American Heart Association guideline on Cardiovascular Prevention focuses on the benefits of a Plant-Based Diet and the Mediterranean diet. In addition to these recommendations, several other diets exist with variable long-term cardiovascular outcomes. In recent years, the ketogenic and intermittent fasting diets have been emerging and have garnered their own respective followings as weight loss strategies, and we will include them in our discussion of the potential long-term benefits related to cardiovascular risks. As the guidelines emphasize, all of the diets we will cover throughout this review must be discussed at the level of the individual patient with their primary care provider, and cannot be exercised without informed consent regarding the potential outcomes. Further research is required, and caution is advised before prescribing any of these diets to patients in the long-term, due to the potential to exacerbate cardiovascular risk factors.

Dietary interventions have not been effective in the treatment of multiple sclerosis (MS). Here, we show that periodic 3-day cycles of a fasting mimicking diet (FMD) are effective in ameliorating demyelination and symptoms in a murine experimental autoimmune encephalomyelitis (EAE) model. The FMD reduced clinical severity in all mice and completely reversed symptoms in 20% of animals. These improvements were associated with increased corticosterone levels and regulatory T (Treg) cell numbers and reduced levels of pro-inflammatory cytokines, TH1 and TH17 cells, and antigen-presenting cells (APCs). Moreover, the FMD promoted oligodendrocyte precursor cell regeneration and remyelination in axons in both EAE and cuprizone MS models, supporting its effects on both suppression of autoimmunity and remyelination. We also report preliminary data suggesting that an FMD or a chronic ketogenic diet are safe, feasible, and potentially effective in the treatment of relapsing-remitting multiple sclerosis (RRMS) patients (NCT01538355).

Prolonged fasting (PF) promotes stress resistance, but its effects on longevity are poorly understood. We show that alternating PF and nutrient-rich medium extended yeast lifespan independently of established pro-longevity genes. In mice, 4 days of a diet that mimics fasting (FMD), developed to minimize the burden of PF, decreased the size of multiple organs/systems, an effect followed upon re-feeding by an elevated number of progenitor and stem cells and regeneration. Bi-monthly FMD cycles started at middle age extended longevity, lowered visceral fat, reduced cancer incidence and skin lesions, rejuvenated the immune system, and retarded bone mineral density loss. In old mice, FMD cycles promoted hippocampal neurogenesis, lowered IGF-1 levels and PKA activity, elevated NeuroD1, and improved cognitive performance. In a pilot clinical trial, three FMD cycles decreased risk factors/biomarkers for aging, diabetes, cardiovascular disease, and cancer without major adverse effects, providing support for the use of FMDs to promote healthspan.

Sterile inflammation occurs when inflammatory proteins are increased in blood and tissues by nonpathogenic states and is a double-edged sword depending on its cause (stress, injury, or disease), duration (transient versus chronic), and inflammatory milieu. Short-term fasting can exert a host of health benefits through unknown mechanisms. The following experiment tested if a 24 h fast would modulate basal and stress-evoked sterile inflammation in plasma and adipose. Adult male F344 rats were either randomized to ad libitum access to food or fasted for 24 h prior to 0 (control), 10, or 100, 1.5 mA-5 s intermittent, inescapable tail shocks (IS). Glucose, nonesterified free fatty acids (NEFAs), insulin, leptin, and corticosterone were measured in plasma and tumor necrosis factor- (TNF-) α, interleukin- (IL-) 1β, IL-6, and IL-10 in plasma, and subcutaneous, intraperitoneal, and visceral compartments of white adipose tissue (WAT). In control rats, a 24 h fastreduced all measured basal cytokines in plasma and visceral WAT, IL-1β and IL-6 in subcutaneous WAT, and IL-6 in intraperitoneal WAT. In stressed rats (IS), fasting reduced visceral WAT TNF-α, subcutaneous WAT IL-1β, and plasma insulin and leptin. Short-term fasting may thus prove to be a usefuldietary strategy for reducing peripheral inflammatory states associated with visceral obesity and chronic stress.

BACKGROUND:Inflammation within the central nervous system (CNS) is frequently comorbid with anxiety. Importantly, the pro-inflammatory cytokine most commonly associated with anxiety is IL-1β. The bioavailability and activity of IL-1β are regulated by caspase-1-dependent proteolysis vis-a-vis the inflammasome. Thus, interventions regulating the activation or activity of caspase-1 should reduce anxiety especially in states that foster IL-1β maturation.

METHODS:Male C57BL/6j, C57BL/6j mice treated with the capase-1 inhibitor biotin-YVAD-cmk, caspase-1 knockout (KO) mice and IL-1R1 KO mice were fasted for 24h or allowed ad libitum access to food. Immediately after fasting, caspase-1 activity was measured in brain region homogenates while activated caspase-1 was localized in the brain by immunohistochemistry. Mouse anxiety-like behavior and cognition were tested using the elevated zero maze and novel object/object location tasks, respectively.

RESULTS:A 24h fast in mice reduced the activity of caspase-1 in whole brain and in the prefrontal cortex, amygdala, hippocampus, and hypothalamus by 35%, 25%, 40%, 40%, and 40% respectively. A 24h fast also reduced anxiety-like behavior by 40% and increased novel object and object location recognition by 21% and 31%, respectively. IL-1β protein, however, was not reduced in the brain by fasting. ICV administration of YVAD decreased caspase-1 activity in the prefrontal cortex and amygdala by 55%, respectively leading to a 64% reduction in anxiety like behavior. Importantly, when caspase-1 KO or IL1-R1 KO mice are fasted, no fasting-dependent reduction in anxiety-like behavior was observed.

CONCLUSIONS:Results indicate that fasting decrease anxiety-like behavior and improves memory by a mechanism tied to reducing caspase-1 activity throughout the brain.

Hepatic expression of fibroblast growth factor 21 (FGF21), one of the most promising therapeutic candidates for metabolic syndrome, is induced by multiple factors associated with fasting, including cyclic AMP response element-binding protein H (CREBH). Alpha lipoic acid (ALA), a naturally occurring thiol antioxidant, has been shown to induce metabolic changes that are similar to those induced by FGF21, including weight loss and increased energy expenditure. Here, we investigated the effect of ALA on hepatic FGF21 expression. ALA treatment enhanced CREBH and FGF21 mRNA expression and protein abundance in cultured hepatocytes. ALA increased FGF21 promoter activity by up-regulating CREBH expression and increasing CREBH binding to the FGF21 promoter, indicating that ALA up-regulates FGF21 at the transcriptional level. Moreover, inhibition of endogenous CREBH expression by siRNA attenuated ALA-induced FGF21 expression. Finally, treatment of mice with ALA enhanced fasting-induced up-regulation of CREBH and FGF21 in the liver and inhibited feeding-induced suppression of their expression. Consistently, ALA increased serum FGF21 levels in both fasted and fed mice. Collectively, these results indicate that ALA increases hepatic FGF21 expression via up-regulation of CREBH, identifying ALA as a novel positive regulator of FGF21.

Chronic exposure of pancreatic beta-cells to supraphysiologic glucose causes adverse beta-cell dysfunction. Thus, the present study was aimed to investigate the hypothesis that oral administration of resveratrol attenuates hyperglycemia, proinflammatory cytokines and antioxidant competence and protects beta-cell ultrastructure in streptozotocin-nicotinamide-induced diabetic rats. Oral administration of resveratrol (5 mg/kg body weight) to diabetic rats for 30 days showed a significant decline in the levels of blood glucose, glycosylated hemoglobin (HbA1c), TNF-alpha, IL-1beta, IL-6, NF-kappaB p65 unit and nitric oxide (NO) with concomitant elevation in plasma insulin. Further, resveratrol treated diabetic rats elicited a notable attenuation in the levels of lipid peroxides, hydroperoxides and protein carbonyls in both plasma and pancreatic tissues. The diminished activities of pancreatic superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx) and glutathione-S-transferase (GST) as well as the decreased levels of plasma ceruloplasmin, vitamin C, vitamin E and reduced glutathione (GSH) in diabetic rats were reverted to near normalcy by resveratrol administration. Based on histological and ultrastructural observations, it is first-time reported that the oral administration of resveratrol may effectively rescue beta-cells from oxidative damage without affecting their function and structural integrity. The results of the present investigation demonstrated that resveratrol exhibits significant antidiabetic potential by attenuating hyperglycemia, enhancing insulin secretion and antioxidant competence in pancreatic beta-cells of diabetic rats.

Caloric restriction (CR) in experimental animals shows to extend the lifespan of animals with the decreased frequency of age-related diseases. CR also produces beneficial health effects in monkeys and humans. These benefits include improved insulin sensitivity, enhanced stress resistance, decreased cancer incidence, and increased neuronal function and neurogenesis. Several important signal transduction pathways have been implicated in the regulation of the physiological processes of CR leading to increased lifespan. One of these pathways includes the Sirt1 pathway. Sirt1 deacetylates a large number of transcriptional factors and cofactors involved in cell growth, differentiation, stress resistance, oxidative damage, and metabolism. Recently, several studies report that resveratrol and other compounds exogenously activate Sirt1 protein and improve the obesity-associated pathology in mice. In this text, we introduce the recent topics of CR research and discuss the anti-aging effects by CR.

Inflammation plays an important role in diabetes mellitus and its complications. In this context, the negative cross-talk between adipose tissue and skeletal muscle leads to disturbances in muscle cell insulin signalling and induces insulin resistance. Because several studies have shown that energy restriction brings some benefits to diabetes, the aim of the present study was to evaluate the effects of dietary restriction on systemic and skeletal muscle inflammatory biomarkers, such C-reactive protein, adipokines and cytokines, and in insulin resistance in Goto-Kakizaki rats. This is an animal model of spontaneous non-obese type 2 diabetes with strongly insulin resistance and without dyslipidaemia. Animals were maintained during 2 months of dietary restriction (50 %) and were killed at 6 months of age. Some biochemical determinations were done using ELISA and Western blot. Data from the present study demonstrate that in Goto-Kakizaki rats the dietary restriction improved insulin resistance, NEFA levels and adipokine profile and ameliorated inflammatory cytokines in skeletal muscle. These results indicate that dietary restriction in type 2 diabetes enhances adipose tissue metabolism leading to an improved skeletal muscle insulin sensitivity.

Hormesis is defined as a dose-response phenomenon characterized by low-dose stimulation and high-dose inhibition, and has been recognized as representing an overcompensation for mild environmental stress. The beneficial effects of mild stress on aging and longevity have been studied for many years. In experimental animals, mild dietary stress (dietary restriction, DR) without malnutrition delays most age-related physiological changes, and extends maximum and average lifespan. Animal studies have also demonstrated that DR can prevent or lessen the severity of cancer, stroke, coronary heart disease, autoimmune disease, allergy, Parkinson's disease and Alzheimer's disease. The effects of DR are considered to result from hormetic mechanisms. These effects were reported by means of various DR regimens, such as caloric restriction, total-nutrient restriction, alternate-day fasting, and short-term fasting. Mild dietary stress, including restriction of amount or frequency of intake, is the essence of DR. For more than 99% of their history, humans lived as hunter-gatherers and adapted to restrictions in their food supply. On the other hand, an oversufficiency of food for many today has resulted in the current global epidemic of obesity and obesity-related diseases. DR may be used, therefore, as a novel approach for therapeutic intervention in several diseases, when detailed information about effects of mild dietary stress on human health is obtained from clinical trials.

Cancer is the second leading cause of death worldwide and the morbidity is growing in developed countries. According to WHO,>14 million people per year are diagnosed with cancer and about 8 million die. Anti-cancer strategy includes chemo-, immune- and radiotherapy or their combination. Unfortunately, these widely used strategies often have insufficient efficacy and significant toxic effects on healthy cells. Consequently, the improvement of treatment approaches is an important goal. One of promising schemes to enhance the effect of therapy is the restriction of calorie intake or some nutrients. The combination of caloric restriction or its chemical mimetics along with anti-cancer drugs may suppress growth of tumor cells and enhance death of cancer cells. That will allow the dose of therapeutic drugs to be decreased and their toxic effects to be reduced. Here the possibility of using this combinatory therapy as well as the molecular mechanisms underlying this approach will be discussed.

It is widely accepted that caloric restriction (CR) without malnutrition delays the onset of aging and extends lifespan in diverse animal models including yeast, worms, flies, and laboratory rodents. The mechanism underlying this phenomenon is still unknown. We have hypothesized that a reprogramming of energy metabolism is a key event in the mechanism of CR (Anderson and Weindruch 2007). Data will be presented from studies of mice on CR, the results of which lend support to this hypothesis. Effects of long-term CR (but not short-term CR) on gene expression in white adipose tissue (WAT) are overt. In mice and monkeys, a chronic 30% reduction in energy intake yields a decrease in adiposity of approximately 70%. In mouse epididymal WAT, long-term CR causes overt shifts in the gene expression profile: CR increases the expression of genes involved in energy metabolism (Higami et al. 2004), and it down-regulates the expression of more than 50 pro-inflammatory genes (Higami et al. 2006). Whether aging retardation occurs in primates on CR is unknown. We have been investigating this issue in rhesus monkeys subjected to CR since 1989 and will discuss the current status of this project. A new finding from this project is that CR reduces the rate of age-associated muscle loss (sarcopenia) in monkeys (Colman et al. 2008).

Caloric restriction and autophagy-inducing pharmacological agents can prolong lifespan in model organisms including mice, flies, and nematodes. In this study, we show that transgenic expression of Sirtuin-1 induces autophagy in human cells in vitro and in Caenorhabditis elegans in vivo. The knockdown or knockout of Sirtuin-1 prevented the induction of autophagy by resveratrol and by nutrient deprivation in human cells as well as by dietary restriction in C. elegans. Conversely, Sirtuin-1 was not required for the induction of autophagy by rapamycin or p53 inhibition, neither in human cells nor in C. elegans. The knockdown or pharmacological inhibition of Sirtuin-1 enhanced the vulnerability of human cells to metabolic stress, unless they were stimulated to undergo autophagy by treatment with rapamycin or p53 inhibition. Along similar lines, resveratrol and dietary restriction only prolonged the lifespan of autophagy-proficient nematodes, whereas these beneficial effects on longevity were abolished by the knockdown of the essential autophagic modulator Beclin-1. We conclude that autophagy is universally required for the lifespan-prolonging effects of caloric restriction and pharmacological Sirtuin-1 activators.

Caloric restriction (CR), without malnutrition, delays aging and extends life span in diverse species; however, its effect on resistance to illness and mortality in primates has not been clearly established. We report findings of a 20-year longitudinal adult-onset CR study in rhesus monkeys aimed at filling this critical gap in aging research. In a population of rhesus macaques maintained at the Wisconsin National Primate Research Center, moderate CR lowered the incidence of aging-related deaths. At the time point reported, 50% of control fed animals survived as compared with 80% of the CR animals. Furthermore, CR delayed the onset of age-associated pathologies. Specifically, CR reduced the incidence of diabetes, cancer, cardiovascular disease, and brain atrophy. These data demonstrate that CR slows aging in a primate species.

Caloric restriction mimetics (CRMs) mimic the biochemical effects of nutrient deprivation by reducing lysine acetylation of cellular proteins, thus triggering autophagy. Treatment with the CRM hydroxycitrate, an inhibitor of ATP citrate lyase, induced the depletion of regulatory T cells (which dampen anticancer immunity) from autophagy-competent, but not autophagy-deficient, mutant KRAS-induced lung cancers in mice, thereby improving anticancer immunosurveillance and reducing tumor mass. Short-term fasting or treatment with several chemically unrelated autophagy-inducing CRMs, including hydroxycitrate and spermidine, improved the inhibition of tumor growth by chemotherapy in vivo. This effect was only observed for autophagy-competent tumors, depended on the presence of T lymphocytes, and was accompanied by the depletion of regulatory T cells from the tumor bed.

An important discovery of recent years has been that lifestyle and environmental factors affect cancer initiation, promotion and progression, suggesting that many malignancies are preventable. Epidemiological studies strongly suggest that excessive adiposity, decreased physical activity, and unhealthy diets are key players in the pathogenesis and prognosis of many common cancers. In addition, calorie restriction (CR), without malnutrition, has been shown to be broadly effective in cancer prevention in laboratory strains of rodents. Adult-onset moderate CR also reduces cancer incidence by 50% in monkeys. Whether the antitumorigenic effects of CR will apply to humans is unknown, but CR results in a consistent reduction in circulating levels of growth factors, anabolic hormones, inflammatory cytokines and oxidative stress markers associated with various malignancies. Here, we discuss the link between nutritional interventions and cancer prevention with focus on the mechanisms that might be responsible for these effects in simple systems and mammals with a view to developing chemoprevention agents.

Mitochondrial oxidative damage is a basic mechanism of aging, and multiple studies demonstrate that this process is attenuated by calorie restriction (CR). However, the molecular mechanism that underlies the beneficial effect of CR on mitochondrial dysfunction is unclear. Here, we investigated in mice the mechanisms underlying CR-mediated protection against hypoxia in aged kidney, with a special focus on the role of the NAD-dependent deacetylase sirtuin 1 (Sirt1), which is linked to CR-related longevity in model organisms, on mitochondrial autophagy. Adult-onset and long-term CR in mice promoted increased Sirt1 expression in aged kidney and attenuated hypoxia-associated mitochondrial and renal damage by enhancing BCL2/adenovirus E1B 19-kDa interacting protein 3-dependent (Bnip3-dependent) autophagy. Culture of primary renal proximal tubular cells (PTCs) in serum from CR mice promoted Sirt1-mediated forkhead box O3 (Foxo3) deacetylation. This activity was essential for expression of Bnip3 and p27Kip1 and for subsequent autophagy and cell survival of PTCs under hypoxia. Furthermore, the kidneys of aged Sirt1+/- mice were resistant to CR-mediated improvement in the accumulation of damaged mitochondria under hypoxia. These data highlight the role of the Sirt1-Foxo3 axis in cellular adaptation to hypoxia, delineate a molecular mechanism of the CR-mediated antiaging effect, and could potentially direct the design of new therapies for age- and hypoxia-related tissue damage.

Caloric restriction is an established intervention, of which anti-aging effects are scientifically proven. It has pleiotropic effects on the cardiovascular system: vascular protection, improvement of myocardial ischemic tolerance and retardation of cardiac senescence. First, increasing evidence from both experimental and clinical studies supports the concept that "a man is as old as his arteries". Caloric restriction could prevent the progression of atherosclerosis and vascular aging through direct and indirect mechanisms. Second, the hearts of senescent animals are more susceptible to ischemia than those of young animals. We demonstrated that short-term and prolonged caloric restriction confers cardioprotection against ischemia/reperfusion injury in young and aged rodents. Furthermore, we showed that the increase in circulating adiponectin levels and subsequent activation of adenosine monophosphate-activated protein kinase are necessary for the cardioprotection afforded by short-term caloric restriction. In contrast, the mechanisms by which prolonged caloric restriction confers cardioprotection seem more complicated. Adiponectin, nitric oxide synthase and sirtuin may form a network of cardiovascular protection during caloric restriction. Recently, by using genetically engineered mice, we found that, in addition to endothelial nitric oxide synthase, neuronal nitric oxide synthase plays an essential role in the development of cardioprotection afforded by prolonged caloric restriction. Third, long-term caloric restriction has cardiac-specific effects that attenuate the age-associated impairment seen in left ventricular diastolic function. It is possible that long-term caloric restriction partially retards cardiac senescence by attenuating oxidative damage in the aged heart. Overall, we strongly believe that caloric restriction could reduce morbidity and mortality of cardiovascular events in humans. Geriatr Gerontol Int 2011; 11: 143-156.

We have previously reported that significant improvement may be obtained in rheumatoid arthritis patients by fasting followed by a vegetarian diet for one year. The present study was carried out to examine to what extent biochemical and immunological variables changed during the clinical trial of fasting and vegetarian diet. For the patients who were randomised to the vegetarian diet there was a significant decrease in platelet count, leukocyte count, calprotectin, total IgG, IgM rheumatoid factor (RF), C3-activation products, and the complement components C3 and C4 after one month of treatment. None of the measured parameters changed significantly during this period in the group of omnivores. The course of 14 of 15 measured variables favored the vegetarians compared with the omnivores, but the difference was only significant for leukocyte count, IgM RF, and the complement components C3 and C4. Most of the laboratory variables declined considerably in the vegetarians who improved according to clinical variables, indicating a substantial reduction in inflammatory activity. The leukocyte count, however, decreased in the vegetarians irrespective of the clinical results. Thus, the decline in leukocyte count may be attributed to vegetarian diet per se and not to the reduction in disease activity. The results of the present study are in accordance with the findings from the clinical trial, namely that dietary treatment can reduce the disease activity in some patients with rheumatoid arthritis.