Periodic (intermittent) fasting and caloric restriction cure major age related diseases and extend lifespan.
Fasting therapy for treating and preventing disease – current state of evidence. Forsch Komplementmed. 2013;20(6):444-53. doi: 10.1159/000357765. Epub 2013 Dec 16. Michalsen A1, Li C.
Periods of deliberate fasting with restriction of solid food intake are practiced worldwide, mostly based on traditional, cultural or religious reasons. There is large empirical and observational evidence that medically supervised modified fasting (fasting cure, 200-500 kcal nutritional intake per day) with periods of 7-21 days is efficacious in the treatment of rheumatic diseases, chronic pain syndromes, hypertension, and metabolic syndrome. The beneficial effects of fasting followed by vegetarian diet in rheumatoid arthritis are confirmed by randomized controlled trials. Further beneficial effects of fasting are supported by observational data and abundant evidence from experimental research which found caloric restriction and intermittent fasting being associated with deceleration or prevention of most chronic degenerative and chronic inflammatory diseases. Intermittent fasting may also be useful as an accompanying treatment during chemotherapy of cancer. A further beneficial effect of fasting relates to improvements in sustainable lifestyle modification and adoption of a healthy diet, possibly mediated by fasting-induced mood enhancement. Various identified mechanisms of fasting point to its potential health-promoting effects, e.g., fasting-induced neuroendocrine activation and hormetic stress response, increased production of neurotrophic factors, reduced mitochondrial oxidative stress, general decrease of signals associated with aging, and promotion of autophagy. Fasting therapy might contribute to the prevention and treatment of chronic diseases and should be further evaluated in controlled clinical trials and observational studies.
The health pros and cons of continuous versus intermittent calorie restriction: More questions than answers. Malgorzata E. Skaznik-Wikiel∗, Alex J. Polotsky. University of Colorado Anschutz Medical Campus, Department of Obstetrics and Gynecology, 12631 E 17th Avenue, B198-3, Aurora, CO 80045 United States. Maturitas Volume 79, Issue 3, Pages 275–278, November 2014.
Beneficial effects on health of limiting food intake for certain periods of time have been recognized for a long time. While many diets can produce short-term weight loss, most fail to result in a long-lasting impact. Current data suggest that intermittent fasting may be beneficial for overall health and wellbeing. However, the lack of properly designed clinical studies makes it challenging to formulate evidence-based practice recommendations. Potential health risks of drastic changes in food intake are often ignored and might only be revealed after extensive follow-up. This review summarizes the popular intermittent dieting methods and their potential impact on fertility and reproduction.
Fasting: molecular mechanisms and clinical applications. Longo VD1, Mattson MP2. Cell Metab. 2014 Feb 4;19(2):181-92. doi: 10.1016/j.cmet.2013.12.008. Epub 2014 Jan 16.
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.
Interventions that improve body and brain bioenergetics for Parkinson’s disease risk reduction and therapy. Mattson MP. J Parkinsons Dis. 2014;4(1):1-13. doi: 10.3233/JPD-130335.
Studies of Parkinson’s disease (PD) patients, animal models and pathogenic actions of genetic mutations that cause familial PD have established that neuronal bioenergetics are compromised with brainstem and midbrain monoaminergic neurons being particularly vulnerable. Peripheral insulin resistance and diabetes in midlife may increase the risk of PD, and diet and lifestyle changes that increase insulin sensitivity (exercise and intermittent energy restriction) can counteract neurodegenerative processes and improve functional outcome in animal models. Insulin sensitizing glucagon-like peptide 1 (GLP-1) analogs are beneficial in animal models of PD, and the results of an initial clinical trial in PD patients are promising. In addition to improving peripheral and brain energy metabolism, exercise, intermittent energy restriction and GLP-1 analogs may bolster neuronal adaptive stress response pathways that enhance neurotrophic signaling, DNA repair, proteostasis and mitochondrial biogenesis.
Overview of caloric restriction and ageing. Masoro EJ. Mech Ageing Dev. 2005 Sep;126(9):913-22.
It has been known for some 70 years that restricting the food intake of laboratory rats extends their mean and maximum life span. In addition, such life extension has been observed over the years in many other species, including mice, hamsters, dogs, fish, invertebrate animals, and yeast. Since this life-extending action appears to be due to a restricted intake of energy, this dietary manipulation is referred to as caloric restriction (CR). CR extends life by slowing and/or delaying the ageing processes. The underlying biological mechanism responsible for the life extension is still not known, although many hypotheses have been proposed. The Growth Retardation Hypothesis, the first proposed, has been tested and found wanting. Although there is strong evidence against the Reduction of Body Fat Hypothesis, efforts have recently been made to resurrect it. While the Reduction of Metabolic Rate Hypothesis is not supported by experimental findings, it nevertheless still has advocates. Currently, the most popular concept is the Oxidative Damage Attenuation Hypothesis; the results of several studies provide support for this hypothesis, while those of other studies do not. The Altered Glucose-Insulin System Hypothesis and the Alteration of the Growth Hormone-IGF-1 Axis Hypothesis have been gaining favor, and data have emerged that link these two hypotheses as one. Thus, it may now be more appropriate to refer to them as the Attenuation of Insulin-Like Signaling Hypothesis. Finally, the Hormesis Hypothesis may provide an overarching concept that embraces several of the other hypotheses as merely specific examples of hormetic processes. For example, the Oxidative Damage Attenuation Hypothesis probably addresses only one of likely many damaging processes that underlie aging. It is proposed that low-intensity stressors, such as CR, activate ancient hormetic defense mechanisms in organisms ranging from yeast to mammals, defending them against a variety of adversities and, when long-term, retarding senescent processes.
Findings on the effect of intermittent fasting on the diabetic syndrome Intermittent fasting modulation of the diabetic syndrome in sand rats. III. Post-mortem investigations. Belkacemi L, Selselet-Attou G, Bulur N, Louchami K, Sener A, Malaisse WJ.: Int J Mol Med. 2011 Jan;27(1):95-102.
The present report concerns several post-mortem variables examined in sand rats that were either maintained on a vegetal diet (control animals) or exposed first during a 20-day transition period to a mixed diet consisting of a fixed amount of a hypercaloric food and decreasing amounts of the vegetal food and then to a 30-day experimental period of exposure to the hypercaloric food. During the latter period, all animals were either given free access to food or fasting daily for 15 h, i.e. from 5.00 p.m. to 8.00 a.m. The body weight, liver wet weight, pancreas wet weight, plasma glucose and haemoglobin A1c concentration, plasma insulin concentration, insulinogenic index, insulin resistance HOMA, plasma cholesterol and triglyceride concentration, liver triglyceride and phospholipid content were all measured. Pancreatic islet (insulin, GLUT2) and liver (lipid droplets) histology were also examined. The main findings consisted in a lower body weight of fasting than non-fasting animals, a higher liver weight in non-diabetic and diabetic rats than in control non-fasting (but not so in fasting) animals, a decrease of pancreas weight in non-diabetic and diabetic as distinct from control animals, a fasting-induced decrease in plasma glucose, plasma insulin and insulin resistance HOMA, plasma cholesterol and triglyceride concentration and triglyceride liver content.
Reprogramming of Differentiated Cells to Stem-Like Self-Renewal States] Pharmacological Mimicking of Caloric Restriction Elicits Epigenetic Reprogramming of Differentiated Cells to Stem-Like Self-Renewal States. Oliveras-Ferraros C, Vazquez-Martin A, Menendez JA.: Rejuvenation Res. 2010 Nov 3.
Abstract Networks of oncogenes and tumor suppressor genes that control cancer cell proliferation also regulate stem cell renewal and possibly stem cell aging. Because (de)differentiation processes might dictate tumor cells to retrogress to a more stem-like state in response to aging-relevant epigenetic and/or environmental players, we recently envisioned that cultured human cancer cells might be used as reliable models to test the ability of antiaging interventions for promoting the initiation and maintenance of self-renewing divisions. Cancer cell lines naturally bearing undetectable amounts of stem/progenitor-like cell populations were continuously cultured in the presence of the caloric restriction mimetic metformin for several months. Microarray technology was employed to profile expression of genes related to the identification, growth, and differentiation of stem cells. Detection of functionally related gene groups using a pathway analysis package provided annotated genetic signatures over- and underexpressed in response to pharmacological mimicking of caloric restriction. By following this methodological approach, we recently obtained data fitting a model in which, in response to chronic impairment of cellular bioenergetics imposed by metformin-induced mitochondrial uncoupling as assessed by the phosphorylation state of cAMP-response element binding protein (CREB), tumor cells can retrogress from a differentiated state to a more CD44(+) stem-like primitive state epigenetically governed by the Polycomb-group suppressor BMI1-a crucial “stemness” gene involved in the epigenetic maintenance of adult stem cells. These findings might provide a novel molecular avenue to investigate if antiaging benefits from caloric restriction mimetics might relate to their ability to epigenetically reprogram stemness while prolonging the capacity of stem-like cell states to proliferate, differentiate, and replace mature cells in adult aging tissues.
Reduction of oxidative stress through caloric restriction. Calorie Restriction Reduces Oxidative Stress by SIRT3-Mediated SOD2 Activation. Qiu X, Brown K, Hirschey MD, Verdin E, Chen D.: Cell Metab. 2010 Dec 1;12(6):662-7.
A major cause of aging and numerous diseases is thought to be cumulative oxidative stress, resulting from the production of reactive oxygen species (ROS) during respiration. Calorie restriction (CR), the most robust intervention to extend life span and ameliorate various diseases in mammals, reduces oxidative stress and damage. However, the underlying mechanism is unknown. Here, we show that the protective effects of CR on oxidative stress and damage are diminished in mice lacking SIRT3, a mitochondrial deacetylase. SIRT3 reduces cellular ROS levels dependent on superoxide dismutase 2 (SOD2), a major mitochondrial antioxidant enzyme. SIRT3 deacetylates two critical lysine residues on SOD2 and promotes its antioxidative activity. Importantly, the ability of SOD2 to reduce cellular ROS and promote oxidative stress resistance is greatly enhanced by SIRT3. Our studies identify a defense program that CR provokes to reduce oxidative stress and suggest approaches to combat aging and oxidative stress-related diseases.
Adipose and liver stress reduced through caloric restriction. Caloric restriction decreases ER stress in liver and adipose tissue in ob/ob mice. Tsutsumi A, Motoshima H, Kondo T, Kawasaki S, Matsumura T, Hanatani S, Igata M, Ishii N, Kinoshita H, Kawashima J, Taketa K, Furukawa N, Tsuruzoe K, Nishikawa T, Araki E.: Biochem Biophys Res Commun. 2010 Dec 3.
Endoplasmic reticulum (ER) stress plays a crucial role in the development of insulin resistance and diabetes. Although caloric restriction (CR) improves obesity-related disorders, the effects of CR on ER stress in obesity remain unknown. To investigate how CR affects ER stress in obesity, ob/ob mice were assigned to either ad libitum (AL) (ob-AL) or CR (ob-CR) feeding (2 g food/day) for 1-4 weeks. The body weight (BW) of ob-CR mice decreased to the level of lean AL-fed littermates (lean-AL) within 2 weeks. BW of lean-AL and ob-CR mice was less than that of ob-AL mice. Ob-CR mice showed improved glucose tolerance and hepatic insulin action compared with ob-AL mice. Levels of ER stress markers such as phosphorylated PKR-like ER kinase (PERK) and eukaryotic translation initiation factor 2α and the mRNA expression of activating transcription factor 4 were significantly higher in the liver and epididymal fat from ob-AL mice compared with lean-AL mice. CR for 2 and 4 weeks significantly reduced all of these markers to less than 35% and 50%, respectively, of the levels in ob-AL mice. CR also significantly reduced the phosphorylation of insulin receptor substrate (IRS)-1 and c-Jun NH(2)-terminal kinase (JNK) in ob/ob mice. The CR-mediated decrease in PERK phosphorylation was similar to that induced by 4-phenyl butyric acid, which reduces ER stress in vivo. In conclusion, CR reduced ER stress and improved hepatic insulin action by suppressing JNK-mediated IRS-1 serine-phosphorylation in ob/ob mice.
Improved post-ischemic recovery and cardiac metabolism through caloric restriction] Improved cardiac metabolism and activation of the RISK pathway contributes to improved post-ischemic recovery in calorie restricted mice. Sung MM, Soltys CL, Masson G, Boisvenue JJ, Dyck JR.: J Mol Med. 2010 Dec 8.
Recent evidence has suggested that activation of AMP-activated protein kinase (AMPK) induced by short-term caloric restriction (CR) protects against myocardial ischemia-reperfusion (I/R) injury. Because AMPK plays a central role in regulating energy metabolism, we investigated whether alterations in cardiac energy metabolism contribute to the cardioprotective effects induced by CR. Hearts from control or short-term CR mice were subjected to ex vivo I/R and metabolism, as well as post-ischemic functional recovery was measured. Even in the presence of elevated levels of fatty acids, CR significantly improved recovery of cardiac function following ischemia. While rates of fatty acid oxidation or glycolysis from exogenous glucose were similar between groups, improved functional recovery post-ischemia in CR hearts was associated with high rates of glucose oxidation during reperfusion compared to controls. Consistent with CR improving energy supply, hearts from CR mice had increased ATP levels, as well as lower AMPK activity at the end of reperfusion compared to controls. Furthermore, in agreement with the emerging concept that CR is a non-conventional form of pre-conditioning, we observed a significant increase in phosphorylation of Akt and Erk1/2 at the end of reperfusion. These data also suggest that activation of the reperfusion salvage kinase (RISK) pathway also contributes to the beneficial effects of CR in reducing post-ischemia contractile dysfunction. These findings also suggest that short-term CR improves post-ischemic recovery by promoting glucose oxidation, and activating the RISK pathway. As such, pre-operative CR may be a clinically relevant strategy for increasing ischemic tolerance of the heart. More experimental and clinical evidence exists that intermittent fasting (IF) extends lifespan and delays the onset of major age-related diseases. IF is a pattern of eating that alternates between periods of fasting (usually meaning consumption of water and sometimes low-calorie drinks such as black coffee) and non-fasting. There is evidence suggesting that intermittent fasting may have beneficial effects on the health and longevity of animals—including humans—that are similar to the effects of caloric restriction (CR). There is currently no consensus as to the degree to which this is simply due to fasting or due to an (often) concomitant overall decrease in calories, but recent studies have shown support for the former. Alternate-day calorie restriction may prolong life span. Intermittent fasting and caloric restriction are forms of dietary restriction (DR), which is sometimes referred to as dietary energy restriction (DER). Scientific study of intermittent fasting in rats (and anecdotally in humans) was carried out at least as early as 1943. A specific form of intermittent fasting is alternate day fasting (ADF), also referred to as every other day fasting (EOD), or every other day feeding (EODF), a 48-hour routine typically composed of a 24-hour fast followed by a 24-hour non-fasting period. Studies Several formal and informal studies since the 1930s are discussed in a 2013 Scientific American article. The effects of fasting in general, and in diabetes and on the brain were discussed in New Scientist in 2013. Animal studies The 1945 study by Carlson and Hoelzel, cited above, found that the apparent life span of rats in the study was increased by intermittent fasting. Tests in which a group of 33 rats were allowed the same food ad libitum and groups of 37, 37, and 30 rats were fasted one day in four, three, and two days, respectively, after the age of 42 days, showed that the optimum amount of fasting appeared to be fasting one day in three; this increased the life span of littermate males by about 20% and littermate females by about 15%. However, the pre-experimental condition of the individual rats was also found to be an important factor in determining the life spans. No drastic retardation of growth was produced by the intermittent fasting, but the development of mammary tumours was retarded in proportion to the amount of fasting. A number of subsequent studies have shown beneficial effects of intermittent fasting in animals: “Reduced serum glucose and insulin levels and increased resistance of neurons in the brain to excitotoxic stress.” Intermittent fasting was found to “Enhance cardiovascular and brain functions and improve several risk factors for coronary artery disease and stroke including a reduction in blood pressure and increased insulin sensitivity” and that “cardiovascular stress adaptation is improved and heart rate variability is increased in rodents” and that “rodents maintained on an IF regimen exhibit increased resistance of heart and brain cells to ichemic injury in experimental models of myocardial infarction and stroke.”. It may “ameliorate age-related deficits in cognitive function” in mice. A correlation between intermittent fasting and significantly improved biochemical parameters associated with the development of diabetic nephropathy. Resistance in mice to the effects of gamma irradiation.. Lifespan increases of 40.4% and 56.6% in C. elegans for alternate day (24-hour) and every second day (48-hour) fasting, respectively, as compared to an ad libitum diet.. Rats showed markedly improved long-term survival after chronic heart failure via pro-angiogenic, anti-apoptotic, and anti-re-modeling effects. “The findings in animals suggest that alternatice day fasting (ADF) may effectively modulate several risk factors, thereby preventing chronic disease, and that ADF may modulate disease risk to an extent similar to that of CR. More research is required to establish definitively the consequences of ADF.” ADF in rats “prolongs life span and promotes numerous health benefits in rodents, including tissue protection from ichemic damage” but also has negative effects including causing “myocardial hypotrophy, cardiac fibrosis, diastolic dysfunction, and a reduction of cardiac reserve.”
Human studies. Studies on humans suggest possible benefits: Intermittent fasting may function as a form of nutritional hormesis.. Alternate-day fasting may encourage fat-oxidation.. Alternate-day fasting may reduce body weight, LDL, and triglyceride levels to the same degree regardless of maintenance of low fat or high fat diet on the feeding day.
Human diet. A number of individuals are experimenting with different varieties of intermittent fasting as a dietary regimen. In this context, shorthand such as “20/4″ is used to denote a repeating pattern of 20 hours of fasting followed by 4 hours of non-fasting. For example, “Fast-5″ is a book promoting a regimen equivalent to “19/5″. Other alternatives include “16/8″ and “15/9″. In common usage, intermittent fasting describes any diet that includes a period of fasting and a period of non-fasting, even if the diet involves consuming a limited amount of calorie-containing beverages such as coffee or tea during the fasting period. This contrasts with scientific usage of the term, in which no calories are consumed during the fasting period. Another variation on intermittent fasting is to consume limited calories (e.g., 20% of normal) rather than none at all on fasting days – so-called ‘modified fasting’. This regimen may provide many of the benefits of intermittent fasting while being much more acceptable and likely to be adhered to. Another possibility is eating only one meal per day without caloric restriction. When overall calorie intake is not reduced, this diet worsens some cardiovascular disease risk factors. The BBC2 Horizon documentary Eat, Fast & Live Longer showed another plan: during days of fasting, people eat 400–500 kcal (women) or 500–600 kcal (men), and during feed days, the diet was unrestricted. This was done either alternately (one day fasting, one day feeding) or by fasting two days per week: the 5:2 diet.
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