O le faʻataʻitaʻiina o taumafa faʻamatalaga

Malamalama i le ProLon' Fasting Mimicking Diet

Fasting is associated with numerous health benefits; from weight loss to longevity. There are many different types of fasting methods, such as intermittent fasting. The fasting mimicking diet allows you to experience the benefits of traditional fasting without depriving your body of food. The main difference of the FMD is that instead of completely eliminating all food for several days or even weeks, you only restrict your calorie intake for five days out of the month. The FMD can be practiced once a month to promote well-being.

E ui e mafai e se tasi ona mulimuli i le FMD ia latou lava, le ProLon O le anapogi anapogi o meaʻai e ofoina atu ai le polokalama o le taumafataga o le 5-aso ua uma ona siakiina ma faailogaina mo aso taitasi ma e teu meaʻai e te manaʻomia mo le FMD i fuainumera maʻoti ma faʻapotopotoga. O le taumafataga o le taumafataga o le saunia lea e faʻatau ma faigofie-i-sauniuni, meaʻai faʻatoʻaga, e aofia ai faʻamau, sou, snack, supplements, mea inu inu, ma teas. O oloa o loʻo faʻatulagaina faasaienisi ma le tofo tele. A o lei amataina le ProLon` anapogi mimicking meaai, 5-aso taumafataga polokalama, faamolemole ia mautinoa e te talanoa i se fomai tausi soifua maloloina e saili ai pe saʻo le FMD mo oe. O le faʻamoemoega o le suʻesuʻega suʻesuʻeina i lalo o le faʻaalia lea o mea faʻavae mole mole ma faʻamatalaga o le anapogi i le FMD.

Anapogi: Faʻamatalaga Faʻamataʻu ma Talosaga Fomaʻi

Fasting has been practiced for millennia, but only recently studies have shed light on its role in adaptive cellular responses that reduce oxidative damage and inflammation, optimize energy metabolism and bolster cellular protection. In lower eukaryotes, chronic fasting extends longevity in part by reprogramming metabolic and stress resistance pathways. In rodents intermittent or periodic fasting protects against diabetes, cancers, heart disease and neurodegeneration, while in humans it helps reduce obesity, hypertension, asthma and rheumatoid arthritis. Thus, fasting has the potential to delay aging and help prevent and treat diseases while minimizing the side effects caused by chronic dietary interventions.

faʻatomuaga

In humans, fasting is achieved by ingesting no or minimal amounts of food and caloric beverages for periods that typically range from 12 hours to three weeks. Many religious groups incorporate periods of fasting into their rituals including Muslims who fast from dawn until dusk during the month of Ramadan, and Christians, Jews, Buddhists and Hindus who traditionally fast on designated days of the week or calendar year. In many clinics, patients are now monitored by physicians while undergoing water only or very low calorie (less than 200 kcal/day) fasting periods lasting from 1 week or longer for weight management, and for disease prevention and treatment. Fasting is distinct from caloric restriction (CR) in which the daily caloric intake is reduced chronically by 20�40%, but meal frequency is maintained. Starvation is instead a chronic nutritional insufficiency that is commonly used as a substitute for the word fasting, particularly in lower eukaryotes, but that is also used to define extreme forms of fasting, which can result in degeneration and death. We now know that fasting results in ketogenesis, promotes potent changes in metabolic pathways and cellular processes such as stress resistance, lipolysis and autophagy, and can have medical applications that in some cases are as effective as those of approved drugs such as the dampening of seizures and seizure-associated brain damage and the amelioration of rheumatoid arthritis (Bruce-Keller et al., 1999; Hartman et al., 2012; Muller et al., 2001). As detailed in the remainder of this article, findings from well-controlled investigations in experimental animals, and emerging findings from human studies, indicate that different forms of fasting may provide effective strategies to reduce weight, delay aging, and optimize health. Here we review the fascinating and potent effects of different forms of fasting including intermittent fasting (IF, including alternate day fasting, or twice weekly fasting, for example) and periodic fasting (PF) lasting several days or longer every 2 or more weeks. We focus on fasting and minimize the discussion of CR, a topic reviewed elsewhere (Fontana et al., 2010; Masoro, 2005).

Lesona mai Mea Faigofie

The remarkable effects of the typical 20�40% CR on aging and diseases in mice and rats are often viewed as responses evolved in mammals to adapt to periods of limited availability of food (Fontana and Klein, 2007; Fontana et al., 2010; Masoro, 2005; Weindruch and Walford, 1988). However, the cellular and molecular mechanisms responsible for the protective effects of CR have likely evolved billions of years earlier in prokaryotes attempting to survive in an environment largely or completely devoid of energy sources while avoiding age-dependent damage that could compromise fitness. In fact, E. coli switched from a nutrient rich broth to a calorie-free medium survive 4 times longer, an effect reversed by the addition of various nutrients but not acetate, a carbon source associated with starvation conditions (Figure 1A) (Gonidakis et al., 2010). The effect of rich medium but not acetate in reducing longevity raises the possibility that a ketone body-like carbon source such as acetate may be part of an �alternate metabolic program� that evolved billions of years ago in microorganisms and that now allows mammals to survive during periods of food deprivation by obtaining much of the energy by catabolizing fatty acids and ketone bodies including acetoacetate and ?-hydroxybutyrate (Cahill, 2006).

In the yeast S. cerevisiae, switching cells from standard growth medium to water also causes a consistent 2-fold chronological lifespan extension as well as a major increase in the resistance to multiple stresses (Figure 1B) (Longo et al., 1997; Longo et al., 2012). The mechanisms of food deprivation-dependent lifespan extension involve the down-regulation of the amino acid response Tor-S6K (Sch9) pathway as well as of the glucose responsive Ras-adenylate cyclase-PKA pathway resulting in the activation of the serine/threonine kinase Rim15, a key enzyme coordinating the protective responses (Fontana et al., 2010). The inactivation of Tor-S6K, Ras-AC-PKA and activation of Rim15 result in increased transcription of genes including superoxide dismutases and heat shock proteins controlled by stress responsive transcription factors Msn2, Msn4 and Gis1, required for the majority of the protective effects caused by food deprivation (Wei et al., 2008). Notably, when switched to food deprivation conditions, both bacteria and yeast enter a hypometabolic mode that allows them to minimize the use of reserve carbon sources and can also accumulate high levels of the ketone body-like acetic acid, analogously to mammals.

Another major model organism in which fasting extends lifespan is the nematode C. elegans. Food deprivation conditions achieved by feeding worms little or no bacteria, lead to a major increase in lifespan (Figure 1C) (Kaeberlein et al., 2006; Lee et al., 2006), which requires AMPK as well as the stress resistance transcription factor DAF-16, similarly to the role of transcription factors Msn2/4 and Gis1 in yeast and FOXOs in flies and mammals (Greer et al., 2007). Intermittent food deprivation also extends lifespan in C. elegans by a mechanism involving the small GTPase RHEB-1 (Honjoh et al., 2009).

I lago, o le tele o suʻesuʻega o loʻo faailoa mai ai o le faʻatafunaina o mea taumafa e le afaina ai le ola vavalalata (Grandison et al., 2009). Ae peitaʻi, o le faʻaitiitia o taumafa poʻo le taumafa o taumafa na faʻaalia i taimi uma e faʻalautele le umi o le Drosophila (Piper ma Partridge, 2007) e fai mai o lago e mafai ona manuia mai le faʻasaina o mea taumafa ae atonu e nofouta i vaitau pupuu.

Faʻatasi ai, o nei faʻamatalaga e iloa ai o le fafagaina o taumafa e mafai ona oʻo i aafiaga o le ola umi i le tele o ituaiga meaola, ae ia faʻamaonia foi o mea eseese faʻalapotopotoga e eseese tali i anapogi.

Tali Tali Atu i le Anapogi i Mamanu

In most mammals, the liver serves as the main reservoir of glucose, which is stored in the form of glycogen. In humans, depending upon their level of physical activity, 12 to 24 hours of fasting typically results in a 20% or greater decrease in serum glucose and depletion of the hepatic glycogen, accompanied by a switch to a metabolic mode in which non-hepatic glucose, fat-derived ketone bodies and free fatty acids are used as energy sources (Figures 2 and 3). Whereas most tissues can utilize fatty acids for energy, during prolonged periods of fasting, the brain relies on the ketone bodies ?-hydroxybutyrate and acetoacetate in addition to glucose for energy consumption (Figure 3B). Ketone bodies are produced in hepatocytes from the acetyl-CoA generated from ? oxidation of fatty acids released into the bloodstream by adipocytes, and also by the conversion of ketogenic amino acids. After hepatic glycogen depletion, ketone bodies, fat-derived glycerol, and amino acids account for the gluconeogenesis-dependent generation of approximately 80 grams/day of glucose, which is mostly utilized by the brain. Depending on body weight and composition, the ketone bodies, free fatty acids and gluconeogenesis allow the majority of human beings to survive 30 or more days in the absence of any food and allow certain species, such as king penguins, to survive for over 5 months without food (Eichhorn et al., 2011) (Figure 3C). In humans, during prolonged fasting, the plasma levels of 3-?-hydroxybutyrate are about 5 times those of free fatty acids and acetoacetic acid (Figure 3A and 3B). The brain and other organs utilize ketone bodies in a process termed ketolysis, in which acetoacetic acid and 3-?- hydroxybutyrate are converted into acetoacetyl-CoA and then acetyl-CoA. These metabolic adaptations to fasting in mammals are reminiscent of those described earlier for E. coli and yeast, in which acetic acid accumulates in response to food deprivation (Gonidakis et al., 2010; Longo et al., 2012). In yeast, glucose, acetic acid and ethanol, but not glycerol which is also generated during fasting from the breakdown of fats, accelerate aging (Fabrizio et al., 2005; Wei et al., 2009). Thus, glycerol functions as a carbon source that does not activate the pro-aging nutrient signaling pathways but can be catabolized by cells. It will be important to understand how the different carbon sources generated during fasting affect cellular protection and aging. and to determine whether glycerol, specific ketone bodies or fatty acids can provide nourishment while reducing cellular aging in mammals, a possibility suggested by beneficial effects of a dietary ketone precursor in a mouse model of Alzheimer�s disease (Kashiwaya et al., 2012). It will also be important to study, in various model organisms and humans, how high intake of specific types of fats (medium- vs.

Anapogi ma le Brain

In mammals, severe CR/food deprivation results in a decrease in the size of most organs except the brain, and the testicles in male mice (Weindruch and Sohal, 1997). From an evolutionary perspective this implies that maintenance of a high level of cognitive function under conditions of food scarcity is of preeminent importance. Indeed, a highly conserved behavioral trait of all mammals is to be active when hungry and sedentary when satiated. In rodents, alternating days of normal feeding and fasting (IF) can enhance brain function as indicated by improvements in performance on behavioral tests of sensory and motor function (Singh et al., 2012) and learning and memory (Fontan-Lozano et al., 2007). The behavioral responses to IF are associated with increased synaptic plasticity and increased production of new neurons from neural stem cells (Lee et al., 2002).

Particularly interesting with regards to adaptive responses of the brain to limited food availability during human evolution is brain-derived neurotrophic factor (BDNF). The genes encoding BDNF and its receptor TrkB appeared in genomes relatively recently as they are present in vertebrates, but absent from worms, flies and lower species (Chao, 2000). The prominent roles of BDNF in the regulation of energy intake and expenditure in mammals is highlighted by the fact that the receptors for both BDNF and insulin are coupled to the highly conserved PI3 kinase � Akt, and MAP kinase signaling pathways (Figure 4). Studies of rats and mice have shown that running wheel exercise and IF increase BDNF expression in several regions of the brain, and that BDNF in part mediates exercise- and IF-induced enhancement of synaptic plasticity, neurogenesis and neuronal resistance to injury and disease (see sections on fasting and neurodegeneration below). BDNF signaling in the brain may also mediate behavioral and metabolic responses to fasting and exercise including regulation of appetite, activity levels, peripheral glucose metabolism and autonomic control of the cardiovascular and gastrointestinal systems (Mattson, 2012a, b; Rothman et al., 2012).

Hunger is an adaptive response to food deprivation that involves sensory, cognitive and neuroendocrine changes which motivate and enable food seeking behaviors. It has been proposed that hunger-related neuronal networks, neuropeptides and hormones play pivotal roles in the beneficial effects of energy restriction on aging and disease susceptibility. As evidence, when mice in which the hypothalamic �hunger peptide� NPY is selectively ablated are maintained on a CR diet, the ability of CR to suppress tumor growth is abolished (Shi et al., 2012). The latter study further showed that the ability of CR to elevate circulating adiponectin levels was also compromised in NPY-deficient mice, suggesting a key role for the central hunger response in peripheral endocrine adaptations to energy restriction. Adiponectin levels increase dramatically in response to fasting; and data suggest roles for adiponectin in the beneficial effects of IF on the cardiovascular system (Wan et al., 2010). The hunger response may also improve immune function during aging as ghrelin-deficient mice exhibit accelerated thymic involution during aging, and treatment of middle age mice with ghrelin increases thymocyte numbers and improves the functional diversity of peripheral T cell subsets (Peng et al., 2012). In addition to its actions on the hypothalamus and peripheral endocrine cells, fasting may increase neuronal network activity in brain regions involved in cognition, resulting in the production of BDNF, enhanced synaptic plasticity and improved stress tolerance (Rothman et al., 2012). Thus, hunger may be a critical factor involved in widespread central and peripheral adaptive responses to the challenge of food deprivation for extended time periods.

Anapogi, Faʻasalalau, ma le faʻamaʻi i le Rodent Models

Eseese auala o anapogi ma le matua

The major differences between IF and PF in mice are the length and the frequency of the fast cycles. IF cycles usually last 24 hours and are one to a few days apart, whereas PF cycles last 2 or more days and are at least 1 week apart, which is necessary for mice to regain their normal weight. One difference in the molecular changes caused by different fasting regimes is the effect on a variety of growth factors and metabolic markers, with IF causing more frequent but less pronounced changes than PF. It will be important to determine how the frequency of specific changes such as the lowering of IGF-1 and glucose affect cellular protection, diseases and longevity. The most extensively investigated IF method in animal studies of aging has been alternate day fasting (food is withdrawn for 24 hours on alternate days, with water provided ad libitum) (Varady and Hellerstein, 2007). The magnitude of the effects of alternate day fasting on longevity in rodents depends upon the species and age at regimen initiation, and can range from a negative effect to as much as an 80% lifespan extension (Arum et al., 2009; Goodrick et al., 1990). IF every other day extended the lifespan of rats more than fasting every 3rd or 4th day (Carlson and Hoelzel, 1946). Fasting for 24 hours twice weekly throughout adult life resulted in a significant increase in lifespan of black-hooded rats (Kendrick, 1973). In rats, the combination of alternate day fasting and treadmill exercise resulted in greater maintenance of muscle mass than did IF or exercise alone (Sakamoto and Grunewald, 1987). Interestingly, when rats were maintained for 10 weeks on a PF diet in which they fasted 3 consecutive days each week, they were less prone to hypoglycemia during 2 hours of strenuous swimming exercise as a result of their accumulation of larger intramuscular stores of glycogen and triglycerides (Favier and Koubi, 1988). Several major physiological responses to fasting are similar to those caused by regular aerobic exercise including increased insulin sensitivity and cellular stress resistance, reduced resting blood pressure and heart rate, and increased heart rate variability as a result of increased parasympathetic tone (Figure 2) (Anson et al., 2003; Mager et al., 2006; Wan et al., 2003). Emerging findings suggest that exercise and IF retard aging and some age-related diseases by shared mechanisms involving improved cellular stress adaptation (Stranahan and Mattson, 2012). However, in two different mouse genetic backgrounds, IF did not extend mean lifespan and even reduced lifespan when initiated at 10 months (Goodrick et al., 1990). When initiated at 1.5 months, IF either increased longevity or had no effect (Figure 1D) (Goodrick et al., 1990). These results in rodents point to conserved effects of fasting on lifespan, but also to the need for a much better understanding of the type of fasting that can maximize its longevity effects and the mechanisms responsible for the detrimental effects that may be counterbalancing its anti-aging effects. For example, one possibility is that fasting may be consistently protective in young and middle aged laboratory rodents that are either gaining or maintaining a body weight, but may be detrimental in older animals that, similarly to humans, begin to lose weight prior to their death. Notably, whereas bacteria, yeast and humans can survive for several weeks or more without nutrients, most strains of mice are unable to survive more than 3 days without food.

Anapogi ma le Kanesa

Fasting can have positive effects in cancer prevention and treatment. In mice, alternate day fasting caused a major reduction in the incidence of lymphomas (Descamps et al., 2005) and fasting for 1 day per week delayed spontaneous tumorigenesis in p53-deficient mice (Berrigan et al., 2002). However, the major decrease in glucose, insulin and IGF-1 caused by fasting, which is accompanied by cell death and/or atrophy in a wide range of tissues and organs including the liver and kidneys, is followed by a period of abnormally high cellular proliferation in these tissues driven in part by the replenishment of growth factors during refeeding. When combined with carcinogens during refeeding, this increased proliferative activity can actually increase carcinogenesis and/or pre-cancerous lesions in tissues including liver and colon (Tessitore et al., 1996). Although these studies underline the need for an in depth understanding of its mechanisms of action, fasting is expected to have cancer preventive effects as indicated by the studies above and by the findings that multiple cycles of periodic fasting can be as effective as toxic chemotherapy in the treatment of some cancers in mice (Lee et al., 2012).

In the treatment of cancer, fasting has been shown to have more consistent and positive effects. PF for 2�3 days was shown to protect mice from a variety of chemotherapy drugs, an effect called differential stress resistance (DSR) to reflect the inability of cancer cells to become protected based on the role of oncogenes in negatively regulating stress resistance, thus rendering cancer cells, by definition, unable to become protected in response to fasting conditions (Figure 5) (Raffaghello et al., 2008). PF also causes a major sensitization of various cancer cells to chemo-treatment, since it fosters an extreme environment in combination with the stress conditions caused by chemotherapy. In contrast to the protected state entered by normal cells during fasting, cancer cells are unable to adapt, a phenomenon called differential stress sensitization (DSS), based on the notion that most mutations are deleterious and that the many mutations accumulated in cancer cells promote growth under standard conditions but render them much less effective in adapting to extreme environments (Lee et al., 2012). In mouse models of metastatic tumors, combinations of fasting and chemotherapy that cause DSR and DSS, result in 20 to 60% cancer-free survival compared to the same levels of chemotherapy or fasting alone, which are not sufficient to cause any cancer-free survival (Lee et al., 2012; Shi et al., 2012). Thus, the idea that cancer could be treated with weeks of fasting alone, made popular decades ago, may be only partially true, at least for some type of cancers, but is expected to be ineffective for other types of cancers. The efficacy of long-term fasting alone (2 weeks or longer) in cancer treatment will need to be tested in carefully designed clinical trials in which side effects including malnourishment and possibly a weakened immune system and increased susceptibility to certain infections are carefully monitored. By contrast, animal data from multiple laboratories indicate that the combination of fasting cycles with chemotherapy is highly and consistently effective in enhancing chemotherapeutic index and has high translation potential. A number of ongoing trials should soon begin to determine the efficacy of fasting in enhancing cancer treatment in the clinic.

Anapogi ma Neurodegeneration

Pe a fa'atusatusa i fa'atonuga e fafaga fa'a- libitum, o isumu ma isumu o lo'o tausia ile mea'ai IF o lo'o fa'aalia ai le fa'aitiitia o le fa'aleagaina o le neuronal ma le fa'aleagaina, ma le itiiti ifo o fa'amaoniga ile fa'ata'ita'iga o le fa'ama'i o le Alzheimer (AD), le ma'i Parkinson (PD) ma le ma'i o Huntington. (HD). O nei faʻataʻitaʻiga e aofia ai mice transgenic faʻaalia mutant genes tagata e mafua ai le pule sili AD (amyloid precursor protein and presenilin-1) ma frontotemporal lobe dementia (Tau) (Halagappa et al., 2007), PD (?-synuclein) (Griffioen et al. , 2012) ma le HD (huntingtin) (Duan et al., 2003), faʻapea foʻi ma faʻataʻitaʻiga faʻavae neurotoxin e fetaui ma AD, PD ma HD (Bruce-Keller et al., 1999; Duan ma Mattson, 1999). O manu o loʻo i luga o se meaʻai IF e sili atu le lelei nai lo le faʻatonuina o meaʻai pe a maeʻa manuʻa tuga e aofia ai le faoa faamalosi o le epileptic, stroke, ma manuʻa o le faiʻai ma manuʻa (Arumugam et al., 2010; Bruce-Keller et al., 1999; Plunet et al. al., 2008).

Several interrelated cellular mechanisms contribute to the beneficial effects of IF on the nervous system including reduced accumulation of oxidatively damaged molecules, improved cellular bioenergetics, enhanced neurotrophic factor signaling, and reduced inflammation (Mattson, 2012a). The latter neuroprotective mechanisms are supported by studies showing that IF diets boost levels of antioxidant defenses, neurotrophic factors (BDNF and FGF2) and protein chaperones (HSP-70 and GRP-78), and reduce levels of pro- inflammatory cytokines (TNF?, IL-1? and IL-6) (Figure 4) (Arumugam et al., 2010). IF may also promote restoration of damaged nerve cell circuits by stimulating synapse formation and the production of new neurons from neural stem cells (neurogenesis) (Lee et al., 2002). Interestingly, while beneficial in models of most neurodegenerative conditions, there is evidence that fasting can hasten neurodegeneration in some models of inherited amyotrophic lateral sclerosis, perhaps because the motor neurons affected in those models are unable to respond adaptively to the moderate stress imposed by fasting (Mattson et al., 2007; Pedersen and Mattson, 1999).

Anapogi ma le Misela

Metabolic syndrome (MS), defined as abdominal adiposity, combined with insulin resistance, elevated triglycerides and/or hypertension, greatly increases the risk of cardiovascular disease, diabetes, stroke and AD. Rats and mice maintained under the usual ad libitum feeding condition develop an MS-like phenotype as they age. MS can also be induced in younger animals by feeding them a diet high in fat and simple sugars (Martin et al., 2010). IF can prevent and reverse all aspects of the MS in rodents: abdominal fat, inflammation and blood pressure are reduced, insulin sensitivity is increased, and the functional capacities of the nervous, neuromuscular and cardiovascular systems are improved (Castello et al., 2010; Wan et al., 2003). Hyperglycemia is ameliorated by IF in rodent models of diabetes (Pedersen et al., 1999) and the heart is protected against ischemic injury in myocardial infarction models (Ahmet et al., 2005). A protective effect of fasting against ischemic renal and liver injury occurs rapidly, with 1 � 3 days of fasting improving functional outcome and reducing tissue injury and mortality (Mitchell et al., 2010). Six days on a diet missing just a single essential amino acid such as tryptophan can also elicit changes in metabolism and stress resistance, similar to those caused by fasting, which are dependent on the amino acid sensing kinase Gcn2 (Peng et al., 2012).

Multiple hormonal changes that typify MS in humans a re observed in rodents maintained on high fat and sugar diets including elevated levels of insulin and leptin and reduced levels of adiponectin and ghrelin. Elevated leptin levels are typically reflective of a pro- inflammatory state, whereas adiponectin and ghrelin can suppress inflammation and increase insulin sensitivity (Baatar et al., 2011; Yamauchi et al., 2001). Local inflammation in hypothalamic nuclei that control energy intake and expenditure may contribute to a sustained positive energy balance in MS (Milanski et al., 2012). Fasting results in a lowering of insulin and leptin levels and an elevation of adiponectin and ghrelin levels. By increasing insulin and leptin sensitivity, suppressing inflammation and stimulating autophagy, fasting reverses all the major abnormalities of the MS in rodents (Singh et al., 2009; Wan et al., 2010). Finally, in addition to its many effects on cells throughout the body and brain, IF may elicit changes in the gut microbiota that protect against MS (Tremaroli and Backhed, 2012). Naturally, the challenge of applying fasting-based interventions to treat MS in humans is a major one, as some obese individuals may have difficulties in following IF for long periods.

The ProLon� fasting mimicking diet is a 5-day meal program consisting of scientifically developed and clinically tested, natural ingredients which “trick” the human body into a fasting mode. The FMD is low in carbohydrates as well as proteins and it’s high in fats. The ProLon� fasting mimicking diet promotes a variety of healthy benefits, including weight loss and decreased abdominal fat, all while preserving lead body mass, improved energy levels, softer and healthier looking skin, as well as overall health and wellness. The FMD can promote longevity.

Anapogi, Faʻasalalau, ma Maʻi i Tagata

Anapogi ma Faʻailoga Faigata i le Tupulagaina

Clinical and epidemiological data are consistent wit h an ability of fasting to retard the aging process and associated diseases. Major factors implicated in aging whose generation are accelerated by gluttonous lifestyles and slowed by energy restriction in humans include: 1) oxidative damage to proteins, DNA and lipids; 2) inflammation; 3) accumulation of dysfunctional proteins and organelles; and 4) elevated glucose, insulin and IGF-I, although IGF-1decreases with aging and its severe deficiency can be associated with certain pathologies (Bishop et al., 2010; Fontana and Klein, 2007). Serum markers of oxidative damage and inflammation as well as clinical symptoms are reduced over a period of 2�4 weeks in asthma patients maintained on an alternate day fasting diet (Johnson et al., 2007). Similarly, when on a 2 days/week fasting diet overweight women at risk for breast cancer exhibited reduced oxidative stress and inflammation (Harvie et al., 2011) and elderly men exhibited reductions in body weight and body fat, and improved mood (Teng et al., 2011). Additional effects of fasting in human cells that can be considered as potentially �anti-aging� are inhibition the mTOR pathway, stimulation of autophagy and ketogenesis (Harvie et al., 2011; Sengupta et al., 2010).

Among the major effects of fasting relevant to aging and diseases are changes in the levels of IGF-1, IGFBP1, glucose, and insulin. Fasting for 3 or more days causes a 30% or more decrease in circulating insulin and glucose, as well as rapid decline in the levels of insulin- like growth factor 1 (IGF-1), the major growth factor in mammals, which together with insulin is associated with accelerated aging and cancer (Fontana et al., 2010). In humans, five days of fasting causes an over 60% decrease in IGF-1and a 5-fold or higher increase in one of the principal IGF-1-inhibiting proteins: IGFBP1 (Thissen et al., 1994a). This effect of fasting on IGF-1is mostly due to protein restriction, and particularly to the restriction of essential amino acids, but is also supported by calorie restriction since the decrease in insulin levels during fasting promotes reduction in IGF-1(Thissen et al., 1994a). Notably, in humans, chronic calorie restriction does not lead to a decrease in IGF-1unless combined with protein restriction (Fontana et al., 2008).

IF can be achieved in with a minimal decrease in overall calorie intake if the refeeding period in which subjects overeat is considered. Thus, fasting cycles provide a much more feasible strategy to achieve the beneficial effects of CR, and possibly stronger effects, without the burden of chronic underfeeding and some of the potentially adverse effects associated with weight loss or very low BMIs. In fact, subjects who are moderately overweight (BMI of 25�30) in later life can have reduced overall mortality risk compared to subjects of normal weight (Flegal et al., 2013). Although these results may be affected by the presence of many existing or developing pathologies in the low weight control group, they underline the necessity to differentiate between young individuals and elderly individuals who may use CR or fasting to reduce weight or delay aging. Although extreme dietary interventions during old age may continue to protect from age-related diseases, they could have detrimental effects on the immune system and the ability to respond to certain infectious diseases, wounds and other challenges (Kristan, 2008; Reed et al., 1996). However, IF or PF designed to avoid weight loss and maximize nourishment have the potential to have beneficial effects on infectious diseases, wounds and other insults even in the very old. Nourishment of subjects can be achieved by complementing IF or PF with micro- and macro Studies to test the effect of IF or PF regimens on markers of aging, cancer, cognition and obesity are in progress (V. Longo and M. Mattson).

Anapogi ma le Kanesa

O le anapogi o loʻo i ai le avanoa mo talosaga i le puipuia ma le togafitiga o le kanesa. E ui lava e leai se faʻamaumauga a le tagata e aʻafia i le IF poʻo le PF i le puipuia o le kanesa, o le aʻafiaga i le faʻaitiitia o le IGF-1, insulin ma le kulukose, ma le faateleina o le IGFBP1 ma le tino o le ketone e mafai ona maua ai se siosiomaga puipuia e faʻaitiitia ai le faaleagaina o DNA ma carcinogenesis, i le taimi lava lea e fatuina ai tulaga faʻafefe mo tumutumu o le paʻu ma le mualaʻi (Figure 5). O le mea moni, o le maualuga o le faasalalauina o le IGF-1 e fesootaʻi atu i le faateleina o le lamatiaga o le atiaeina o nisi o kanesa (Chan & al., 2000, Giovannucci et al., 2000) ma tagata taitoatasi i le IGF-1deficiency ogaoga e mafua mai i le tuputupu ae o le senate o le hormone, Guevara-Aguirre et al., 2011; Sheva ma Laron, 2007, Steuerman et al., 2011). E le gata i lea, o le lauga mai nei IGF-1deficient mataupu na puipuia ai le ola o tagata mai le epithelial cell from oxidative stress-induced DNA damage. E le gata i lea, a oʻo loa ina faaleagaina le DNA, o le a sili atu ona lamatia le tino i le tino (Guevara-Aguirre et al., 2011). O le mea lea, o le anapogi e mafai ona puipuia mai le kanesa e ala i le faʻaitiitia o le cellular ma le DNA ae faʻapea foi i le faʻaleleia o le oti o sela muamua.

I se suʻesuʻega muamua o le 10 mataupu ma le tele o feusuaiga, o le tuufaatasiga o le chemotherapy ma le anapogi na mafua ai ona paʻu i le tele o aʻafiaga masani masani a le tagata lava ia e mafua mai i le chemotherapy pe a faatusatusa i mataupu lava e tasi e maua ai le chemotherapy ae i luga o se fua masani (Safdie et al., 2009). O le aʻafiaga o le anapogi i le faʻamaʻi o le chemotherapy ma le alualu i luma o le kanesa o loʻo tofotofoina nei i faamasinoga i totonu o Europa atoa ma le US (0S-08-9, 0S-10-3).

Anapogi ma Neurodegeneration

O lo tatou malamalamaaga nei o le aʻafiaga o IF i luga o le faʻalavelave o le tino ma galuega faʻamalosia e tele lava ina faʻaalia mai suesuega a manu (silasila i luga). O suʻesuʻega faʻasalalau e fuafua ai le aʻafiaga o le anapogi i luga o faiʻai ma gaioiga o faʻamaʻi neurodegenerative ua leai.

Ina ua maeʻa le 3-4 masina, na faʻaleleia e le CR le gaioiga o le mafaufau (mafaufau tautala) i fafine mamafa tele (Kretsch et al., 1997) ma i tagata matutua (Witte et al., 2009). E fa'apena fo'i, pe a fa'atumauina mo le 1 masina i lalo o le 'ai e maualalo le glycemic, na fa'aalia ai le fa'aleleia atili o le fa'atuai o mafaufauga va'aia, su'esu'e cerebrospinal biomarkers o A? metabolism ma faiʻai bioenergetics (Bayer-Carter et al., 2011). O suʻesuʻega e fuaina ai le gaioiga o le mafaufau, faʻaitulagi o faiʻai, gaioiga o fesoʻotaʻiga neural, ma suʻesuʻega biochemical o le sua o le cerebrospinal e fuaina i mataupu a le tagata aʻo leʻi oʻo i se vaitaimi umi ole IF e tatau ona faʻamalamalamaina le aʻafiaga o le IF ile fausaga ma le gaioiga o le faiʻai o le tagata.

Anapogi, Inflammation ma le Maualuga

I tagata, o se tasi o faʻataʻitaʻiga sili ona lelei o aoga aoga o le anapogi umi tumau tasi i le 3 vaiaso o i le togafitiga o rheumatoid gugu (RA). I maliega ma iʻuga i rodents, e i ai sina masalosalo o le vaitaimi o le anapogi uma mumu ma tiga ua faʻaititia i RA tagata mama (Muller et al., 2001). Peitai, a maeʻa ona toe amata le taumafataga masani, e toe foʻi le fula seʻi vagana ua mulimuli mai le vaitaimi o le anapogi e le vegetarian diet (Kjeldsen-Kragh et al., 1991), o se vailaʻau e mafai ona aoga mo le lua tausaga pe sili atu (Kjeldsen-Kragh et al., 1994). O le aoga o lenei auala e lagolagoina e le fa eseʻese faʻatonutonu suʻesuʻega, e aofia ai lua randomized tofotofoga (Muller et al., 2001). O le mea lea, o le anapogi faʻatasi ma se taumafataga vegetarian ma ono maua ma isi teuteuina meaai maua ai aoga aoga i le togafitiga o RA. Faʻafesuiaʻi aso IF na mafua ai foi le taua faʻaititia o le serum TNF? ma ceramides i tagata mamaʻi sela i le 2 masina vaitaimi (Johnson et al., 2007). O le suʻesuʻega mulimuli na faʻaalia ai foi, o faʻailoga o le faʻamamaina o le oxidative e masani ona fesoʻotaʻi ma le fulafula (protein ma lipid oxidation) na matua faʻaititia lava ile tali atu ia IF. O le mea lea, mo le tele o tagata gasegase mafai ma naunau e onosaia umi-anapogi ma ia suia fesuiaʻi a latou taumafataga, anapogi taʻamilosaga ono i ai le ono mafai e le gata faʻaopoopo ae suia foi faʻafomai togafitiga nei.

Water only and other forms of long-term fasting have also been documented to have potent effects on hypertension. An average of 13 days of water only fasting resulted in the achievement of a systolic blood pressure (BP) below 120 in 82% of subjects with borderline hypertension with a mean 20 mm Hg reduction in BP (Goldhamer et al., 2002). BP remained significantly lower compared to baseline even after subjects resumed the normal diet for an average of 6 days (Goldhamer et al., 2002). A small pilot study of patients with hypertension (140 mm and above systolic BP) also showed that 10�11 days of fasting caused a 37�60 mm decrease in systolic BP (Goldhamer et al., 2001). These preliminary studies are promising but underscore the need for larger controlled and randomized clinical studies that focus on periodic fasting strategies that are feasible for a larger portion of the population.

For both hypertension and RA it will be important to develop PF mimicking diets that are as effective as the fasting regimens described above but that are also tolerable by the great majority of patients.

Anapogi ma le Misela

Periodic fasting can reverse multiple features of the metabolic syndrome in humans: it enhances insulin sensitivity, stimulates lipolysis and reduces blood pressure. Body fat and blood pressure were reduced and glucose metabolism improved in obese subjects in response to an alternate day modified fast (Klempel et al., 2013; Varady et al., 2009). Overweight subjects maintained for 6 months on a twice weekly IF diet in which they consumed only 500�600 calories on the fasting days, lost abdominal fat, displayed improved insulin sensitivity and reduced blood pressure (Harvie et al., 2011). Three weeks of alternate day fasting resulted in reductions in body fat and insulin levels in normal weight men and women (Heilbronn et al., 2005) and Ramadan fasting (2 meals/day separated by approximately 12 hours) in subjects with MS resulted in decreased daily energy intake, decreased plasma glucose levels and increased insulin sensitivity (Shariatpanahi et al., 2008). Subjects undergoing coronary angiography who reported that they fasted regularly exhibited a lower prevalence of diabetes compared to non-fasters (Horne et al., 2012). Anti- metabolic syndrome effects of IF were also observed in healthy young men (BMI of 25) after 15 days of alternate day fasting: their whole-body glucose uptake rates increased significantly, levels of plasma ketone bodies and adiponectin were elevated, all of which occurred without a significant decrease in body weight (Halberg et al., 2005). The latter findings are similar to data from animal studies showing that IF can improve glucose metabolism even with little or no weight change (Anson et al., 2003). It will be important to determine if longer fasting periods which promote a robust switch to a fat breakdown and ketone body-based metabolism, can cause longer lasting and more potent effects.

Faaiuga ma Fautuaga

E tusa ai ma faʻamatalaga o loʻo i ai nei mai manu ma suʻesuʻega a le tagata ua faʻamatalaina, matou te manatu o loʻo i ai le malosi tele mo le soifuaga lelei e aofia ai le anapogi masani i le taimi o le olaga matua e faʻamalosia ai le soifua maloloina lelei ma faʻaitiitia le lamatiaga o le tele o faʻamaʻi faʻamaʻi, aemaise lava mo i latou o loʻo mamafa tele ma nonofo mamao. O suʻesuʻega a manu na tusia ai ni aʻafiaga mamafa ma le faʻaaogaina o faʻamaʻi anapogi i luga o le soifua maloloina, ma le faʻaitiitia o le maualuga o le toto, tino o le IGF-I, insulin, glucose, lipine atherogenic ma le mumū. O le anapogi e mafai ona faʻaleleia ai faʻamaʻi faʻamaʻi ma faʻaleleia ai le faʻatinoina o galuega i mamanu o meaola e aofia ai le faʻaleagaina o le myocardial, diabetes, stroke, AD ma le PD. O le tasi auala masani o le faʻatinoina o le anapogi, o le faʻaaogaina lea o tali faʻaogaina i le telefoni feaveai, lea e mafua ai le faʻaleleia atili o le tomai e taulimaina ai faʻafitauli matuia ma faʻafefe ai togafitiga faʻamaʻi. E le gata i lea, i le puipuia o siama mai le faaleagaina o DNA, faʻaitiitia o le tuputupu aʻe o le cell ma faʻaleleia apoptosis o sela na faʻatuina, o le anapogi e mafai ona vave ma / poʻo le puipuia o le faʻavae ma le tuputupu ae o kanesa.

Ae ui i lea, o suʻesuʻega o faiga anapogi e leʻi faia i tamaiti, o tagata matutua ma le mamafa, ma e ono afaina ai le IF ma le PF i nei faitau aofaʻi. O taimi anapogi e umi atu nai lo le 24 itula aemaise lava i latou e 3 pe sili atu aso e tatau ona faia i lalo o le vaavaaiga a se fomaʻi ma sili atu ile falemaʻi. IF- ma le PF-fa'avae auala e tetee atu ai i fa'ama'i o lo'o i ai nei o le mamafa tele, ma'i suka ma fa'ama'i fa'apena e tatau ona tulituliloa i su'esu'ega a tagata ma fuafuaga fa'afoma'i. O le tele o fesuiaiga o `fa'atonuga anapogi' e ono fa'aaogaina mo mataupu mamafa tele e fa'ata'amilo i le autu masani o le aloese mai mea'ai ma meainu caloric mo le itiiti ifo i le 12 - 24 itula i le tasi pe sili atu aso i vaiaso ta'itasi po'o masina, e fa'atatau i le umi, tu'ufa'atasia. faatasi ai ma faamalositino masani. Mo i latou e mamafa tele, e mafai e fomaʻi ona fai atu i a latou gasegase e filifili se faʻalavelave faʻavae anapogi latou te talitonu e mafai ona latou usitaia e faʻatatau i a latou faʻatulagaga i aso taʻitasi ma vaiaso. O faʻataʻitaʻiga e aofia ai le '5: 2' IF meaʻai (Harvie et al., 2011), o le isi aso faʻafouina le anapogi meaai (Johnson et al., 2007; Varady et al., 2009), o le 4-5 aso anapogi poʻo le maualalo kalori. ae o le anapogi fa'asusuga maualuga e fa'ata'ita'i ai mea'ai e ta'i 1-3 masina soso'o ai ma le fa'ase'e o le tasi taumafataga tele i aso uma pe a mana'omia (V. Longo, fa'ata'ita'iga o lo'o faagasolo). O se tasi o atugaluga i le le paleni o meaʻai e fesuiaʻi e pei o meaʻai e maualalo ai le kalori e naʻo le 2 aso o le vaiaso e matauina ai aʻafiaga i luga o le circadian rhythm ma le endocrine ma le gastrointestinal system, lea e iloa e aʻafia i masaniga taumafa. I le 4-6 vaiaso muamua o le fa'atinoina o le fa'atonuga o le anapogi, e tatau ona fa'afeso'ota'i e le foma'i po'o le foma'i mea'ai ua resitalaina ma le ma'i e mata'ituina lo latou alualu i luma ma tu'uina atu fautuaga ma le vaavaaiga.

E mafai fo'i ona fa'atulagaina faiga anapogi mo fa'ama'i fa'apitoa e pei o togafitiga tu'utasi po'o togafitiga fa'aopoopo. O faʻaiʻuga o suʻesuʻega muamua o le IF (anapogi 2 aso i le vaiaso poʻo isi aso uma) i mataupu a le tagata ua fautua mai ai o loʻo i ai se vaitaimi taua o suiga o le 3 - 6 vaiaso i le taimi lea e faʻafetaui ai le faiʻai ma le tino i le mamanu fou o meaʻai ma faʻaleleia lagona. (Harvie et al., 2011; Johnson et al., 2007). E ui lava ina taumatemate, e foliga mai i le vaitaimi o suiga mulimuli e suia ai le neurochemistry o le faiʻai ina ia mafai ai ona faatoilaloina le "vaisu" i le taumafaina masani o meaai i le aso atoa. O le mea moni, o auala eseese o le anapogi e foliga mai e faʻatapulaʻaina le aoga aemaise lava i le matua ma tulaga e ese mai i le oona seʻi vagana ua tuʻufaʻatasia ma meaʻai e pei o le faʻaogaina o le kalori ma le tele o meaʻai maualalo o le Mediterranean poʻo Okinawa (0.8 g protein / Kg o le mamafa o le tino). ), e fesoʻotaʻi pea ma le soifua maloloina ma le ola umi.

I le lumanaʻi, o le a taua tele le tuʻufaʻatasia o faʻamaumauga o le epidemiological, o suʻesuʻega o faitau aofaʻi ola ma a latou meaʻai, o taunuuga mai meaola faʻapitoa e fesoʻotaʻi atu i vaega o mea taumafa faʻapitoa mo mea faʻamuamua ma faʻamaʻi, faatasi ai ma faʻamaumauga mai suʻesuʻega e uiga i le anapogi i totonu o tagata , ia mamanuina ni suʻesuʻega faʻapitoa o suʻesuʻega o loʻo faʻapipiʻi ai le anapogi ma meaai faʻamauina e puipuia ma fiafia. O se malamalamaaga sili atu e uiga i mea mole mole fualaau lea e aʻafia ai le anapogi i ituaiga eseese o le tino ma faʻaʻauʻau e tatau ona taʻitaʻia ai le atinaʻeina o tala faʻasolosolo ma togafitiga faʻafomaʻi mo le tele o faʻafitauli.

Ave le Savali a le Aiga

O le anapogi e faʻatatau ai taumafa e maua ai tutusa lelei o le masani masani ile anapogi e ala i le taofiofia o lau kalori mo le lima aso mai le masina ae le o le faʻaaogaina uma o meaai mo ni nai aso poʻo ni vaiaso foi. Le ProLon O le taumafa anapogi e ofoina atu ai le polokalama o le taumafataga o le 5 lea na faaputuputuina taitoatasi ma faaigoaina i aofaiga saʻo ma tuufaatasiga mo aso taitasi. E ui o le suʻesuʻega suʻesuʻega i luga ua faʻaalia ai le soifua manuia o le anapogi, faamolemole ia mautinoa e te talanoa i se fomai tausi soifua aʻo leʻi amataina ProLon` anapogi mimicking meaai, 5-aso taumafataga polokalama ia iloa pe o le FMD, poʻo soʻo se isi lava meaai, e saʻo mo oe.

O le lomiga lolomiina, faaiu mulimuli o le suesuega sailiiliga na faasinomia i luga na maua i le NIH Public Access Author Tusitala i le PMC Fepuari 4, 2015. O le lautele o a tatou faʻamatalaga e faʻamapulaʻaina i faʻamaʻi faʻasalalau, mataupu faʻalesoifua maloloina o le toto, ma mataupu tau vailaʻau faʻaaogaina. Ina ia toe talanoaina le mataupu, faamolemole ia lagona le saoloto e fesili ia Dr. Alex Jimenez pe faʻafesoʻotaʻi mai i matou 915-850-0900 .

Faʻailoina e Dr. Alex Jimenez

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