Intermittent Fasting

Tricking the body into living longer? (biology, transhumanism)
created: 20 Nov 2011; modified: 09 Oct 2017; status: notes; confidence: possible; importance: 8

Our intuitive mental models are Aristotelian - strength or health are intrinsic qualities which can be developed by certain actions. But the reality is that exercise offers no intrinsic benefit to the body, no more than driving 10,000 miles in a car makes it more fuel-efficient or its tires more robust. Things wear down, in cars and cells. So why is exercise recommended? Because of the biological response to the damage caused by the exercise. Chemical pathways are activated, secretions unleashed, formerly silenced genes suddenly start expressing themselves, and things happen. Chemical cascades can be modified or interrupted by other chemicals, of course. We see proof of this in startling studies, like the consumption of antioxidants destroying the health benefits of exercise; why do antioxidants do that? Because the damage caused by exercise takes, in part, the form of oxidants, and the oxidants trigger some of those chemical pathways; the antioxidants neutralize & eliminate the oxidants, and so those pathways are muted or suppressed.

So much for exercise. Something similar is theorized about the much ballyhooed caloric restriction. It is not the number of calories that has any intrinsic meaning, which finesses any law of physics to enable greater longevity - it is the body’s reactions to the restriction that matters, the changing levels of sirtuin proteins. (Why would evolution not make this reaction the default reaction and would permit the organism to die before it absolutely had to? There are a number of models where aging helps genetic fitness, actually; just another reminder that Nature does not have our best interests at heart.) Presumably some of the pathways could be directly controlled by injecting additional enzymes even as calorie consumption remains intact, and for that reason a number of biotech/pharmacorps have been interested in the sirtuins and other chemicals linked to caloric restriction. All that matters is that the pathways get triggered. A little like a computer - it doesn’t care what a command or file means, it just cares whether the input satisfies whatever entirely arbitrary (from its point of view) criteria the computer holds at that moment.

Are there any other ways to trigger the pathways? There are a few other possible pathways, some in the vein of hormesis (hormesis being another example of how the body’s reaction matters more than the intrinsic properties of whatever has happened to one). Heat shock seems to be one (colder climates linked with longevity).

Curiously, it may be possible to trick the body into thinking there is a caloric shortage - a restriction on calories - just by staggering food consumption. Feast or famine. Eat nothing one day, eat two days’ worth of food the next. Same total calories and nutrients, but possibly different effects?

TODO example of how pathway matters, colder core temp = longer lifespan, but not if achieved through swimming in cold water

In fact, high levels of testosterone, which boost male fertility, are quite bad for long-term survival. … As many dog and cat owners can attest, neutered male animals often live longer than their intact counterparts. Indeed, the evidence supports the notion that male castration might be the ticket to a longer life. Might the same be true of humans?… The historical record is not good enough to determine if eunuchs tend to outlive normal healthy men, but some sad records suggest that they do. A number of years ago castration of men in institutions for the mentally disturbed was surprisingly commonplace. In one study of several hundred men at an unnamed institution in Kansas, the castrated men were found to live on average 14 years longer than their uncastrated … … counterparts. Nevertheless, I doubt that many men —myself included — would choose such a drastic remedy to buy a few extra years.

I’ve been in the field 15 years now, and it’s amazing how theories come and go very quickly. There isn’t a central agreed theory about what aging is at the moment. But I think in the next decade we’ll know, says David Gems, a biologist at the Institute of Healthy Aging at University College London. When it comes to caloric restriction, the thing you have to understand is that we don’t really know how it works. Much of the research is housed at universities and government research labs, but a small antiaging biotech industry (populated largely by current and former academics) has also sprung up.

Calorie restriction exists at the twilight between health enhancement and outright starvation, so a compound would have to be precisely calibrated. If the body gets too strong a signal that energy is low, organs may fail. Scientists have known since a study in 1950 that people who reduce calories by 50 percent can experience depression, apathy, slower movement and other detrimental effects.

Various nutritional, behavioral, and pharmacological interventions have been previously shown to extend life span in diverse model organisms, including Saccharomyces cerevisiae, Caenorhabditis elegans, Drosophila melanogaster, mice, and rats, as well as possibly monkeys and humans. This review aims to summarize published evidence that several longevity-promoting interventions may converge by causing an activation of mitochondrial oxygen consumption to promote increased formation of reactive oxygen species (ROS). These serve as molecular signals to exert downstream effects to ultimately induce endogenous defense mechanisms culminating in increased stress resistance and longevity, an adaptive response more specifically named mitochondrial hormesis or mitohormesis. Consistently, we here summarize findings that antioxidant supplements that prevent these ROS signals interfere with the health-promoting and life-span-extending capabilities of calorie restriction and physical exercise. Taken together and consistent with ample published evidence, the findings summarized here question Harman’s Free Radical Theory of Aging and rather suggest that ROS act as essential signaling molecules to promote metabolic health and longevity.

Extending life span by increasing oxidative stress, Ristowa & Schmeissera 2011

Minimizing carbohydrate (CHO) status in the peri-training period may accelerate the training adaptations normally observed. …these results suggest that (a) meal ingestion prior to daily exercise can modify some of the exercise training-induced adaptations normally seen with endurance training compared to when daily exercise is undertaken in the overnight-fasted state

Fasting before exercise increases fat utilization and lowers the rate of muscle glycogen depletion. Since a 24-h fast also depletes liver glycogen, we were interested in blood glucose homeostasis during exercise after fasting. An experiment was conducted with human subjects to determine the effect of fasting on blood metabolite concentrations during exercise. Nine male subjects ran (70% maximum O2 consumption) two counterbalanced trials, once fed and once after a 23-h fast. Plasma glucose was elevated by exercise in the fasted trial but there was no difference between fed and fasted during exercise. Lactate was significantly higher (P less than 0.05) in fasted than fed throughout the exercise bout. Fat mobilization and utilization appeared to be greater in the fasted trial as evidenced by higher plasma concentrations of free fatty acids, glycerol, and beta-hydroxybutyrate as well as lower respiratory exchange ratio in the fasted trial during the first 30 min of exercise. These results demonstrate that in humans blood glucose concentration is maintained at normal levels during exercise after fasting despite the depletion of liver glycogen.

practical advice on how one can adapt so fasting does not cause mental fog or other performance decreases:

Since May 2003 we have experimented with alternate day calorie restriction, one day consuming 20–50% of estimated daily caloric requirement and the next day ad lib eating, and have observed health benefits starting in as little as two weeks, in insulin resistance, asthma, seasonal allergies, infectious diseases of viral, bacterial and fungal origin (viral URI, recurrent bacterial tonsillitis, chronic sinusitis, periodontal disease), autoimmune disorder (rheumatoid arthritis), osteoarthritis, symptoms due to CNS inflammatory lesions (Tourette’s, Meniere’s) cardiac arrhythmias (PVCs, atrial fibrillation), menopause related hot flashes. We hypothesize that other many conditions would be delayed, prevented or improved, including Alzheimer’s, Parkinson’s, multiple sclerosis, brain injury due to thrombotic stroke atherosclerosis, NIDDM, congestive heart failure.

Our hypothesis is supported by an article from 1957 in the Spanish medical literature which due to a translation error has been construed by several authors to be the only existing example of calorie restriction with good nutrition. We contend for reasons cited that there was no reduction in calories overall, but that the subjects were eating, on alternate days, either 900 calories or 2300 calories, averaging 1600, and that body weight was maintained. Thus they consumed either 56% or 144% of daily caloric requirement. The subjects were in a residence for old people, and all were in perfect health and over 65. Over three years, there were 6 deaths among 60 study subjects and 13 deaths among 60 ad lib-fed controls, non-significant difference. Study subjects were in hospital 123 days, controls 219, highly significant difference.

Currently, a large body of evidence links circadian rhythms with metabolism and feeding regimens. In particular, CR, and possibly also IF, can entrain the master clock located in the suprachiasmatic nuclei (SCN) of the brain hypothalamus. These findings raise the hypothesis that the beneficial effects exerted by these feeding regimens could be mediated, at least in part, through resetting of the circadian clock, thus leading to synchrony in metabolism and physiology. This hypothesis is reinforced by a transgenic mouse model showing spontaneously reduced eating alongside robust circadian rhythms and increased life span.

Resting energy expenditure increases in early starvation, accompanied by an increase in plasma norepinephrine. This increase in norepinephrine seems to be due to a decline in serum glucose and may be the initial signal for metabolic changes in early starvation.

The researchers found that people who fasted regularly had a 58 percent lower risk of coronary disease compared with those who said they didn’t fast, according to the report presented at the American College of Cardiology conference in New Orleans this week….they affirm the results of an earlier, larger study, published in 2008 in The American Journal of Cardiology, that found a similar association between fasting and heart disease among 448 patients….A second, smaller study…30 patients were asked to fast for 24 hours with water only. The scientists used blood tests before and after the fasting period to look at a number of different metabolic markers. Among other changes, they found that levels of human growth hormone, or HGH, surged after fasting — increasing 20 times in men and 13 times in women. The hormone is released by the body in times of starvation to protect lean muscle mass and trigger the body to start burning fat stores.

Semi-Starvation Period (24 weeks): During the 6-month semi-starvation period, each subject’s dietary intake was cut to approximately 1,560 calories per day. Their meals were composed of foods that were expected to typify the diets of people in Europe during the latter stages of the war: potatoes, rutabagas, turnips, bread and macaroni….Among the conclusions from the study was the confirmation that prolonged semi-starvation produces significant increases in depression, hysteria and hypochondriasis as measured using the Minnesota Multiphasic Personality Inventory (MMPI) (a standardized test administered during the experimental period). Indeed, most of the subjects experienced periods of severe emotional distress and depression.[1]:161 There were extreme reactions to the psychological effects during the experiment including self-mutilation (one subject amputated three fingers of his hand with an axe, though the subject was unsure if he had done so intentionally or accidentally).[4] Participants exhibited a preoccupation with food, both during the starvation period and the rehabilitation phase. Sexual interest was drastically reduced, and the volunteers showed signs of social withdrawal and isolation.[1]:123-124 The participants reported a decline in concentration, comprehension and judgment capabilities, although the standardized tests administered showed no actual signs of diminished capacity.

Similarly to calorically restricted animals, IF-fed animals exhibit increased life span in comparison with the ad libitum-fed control, even if there is little or no overall decrease in calories [199,200]. 199. Goodrick CL, Ingram DK, Reynolds MA, Freeman JR, Cider N. Effects of intermittent feeding upon body weight and lifespan in inbred mice: interaction of genotype and age. Mech Ageing Dev. 1990;55:69–87. [PubMed] 200. Mattson MP, Wan R. Beneficial effects of intermittent fasting and caloric restriction on the cardiovascular and cerebrovascular systems. J Nutr Biochem. 2005;16:129–137. [PubMed]

IF-fed animals also exhibit improved glucose metabolism, cardio-protection, neuro-protection [196,201-205], and increased resistance to cancer [197,200]. 196. Anson RM, Guo Z, de Cabo R, Iyun T, Rios M, Hagepanos A, Ingram DK, Lane MA, Mattson MP. Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from calorie intake. Proc Natl Acad Sci U S A. 2003;100:6216–6220. [PMC free article] [PubMed] 197. Descamps O, Riondel J, Ducros V, Roussel AM. Mitochondrial production of reactive oxygen species and incidence of age-associated lymphoma in OF1 mice: effect of alternate-day fasting. Mech Ageing Dev. 2005;126:1185–1191. [PubMed] 201. Contestabile A, Ciani E. Dietary restriction differentially protects from neurodegeneration in animal models of excitotoxicity. Brain Res. 2004;1002:162–166. [PubMed] 202. Mattson MP. Energy intake, meal frequency, and health: a neurobiological perspective. Annu Rev Nutr. 2005;25:237–260. [PubMed] 203. Sharma S, Kaur G. Neuroprotective potential of dietary restriction against kainate-induced excitotoxicity in adult male Wistar rats. Brain Res Bull. 2005;67:482–491. [PubMed] 204. Ahmet I, Wan R, Mattson MP, Lakatta EG, Talan M. Cardioprotection by intermittent fasting in rats. Circulation. 2005;112:3115–3121. [PubMed] 205. Mager DE, Wan R, Brown M, Cheng A, Wareski P, Abernethy DR, Mattson MP. Caloric restriction and intermittent fasting alter spectral measures of heart rate and blood pressure variability in rats. FASEB J. 2006;20:631–637. [PubMed]

IF may also decrease the risk for cardiovascular diseases in humans [206]. 206. Varady KA, Hellerstein MK. Alternate-day fasting and chronic disease prevention: a review of human and animal trials. Am J Clin Nutr. 2007;86:7–13. [PubMed]

One suggested mechanism is stimulation of cellular stress pathways induced by the IF regimen [196,207,208]. 196. Anson RM, Guo Z, de Cabo R, Iyun T, Rios M, Hagepanos A, Ingram DK, Lane MA, Mattson MP. Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from calorie intake. Proc Natl Acad Sci U S A. 2003;100:6216–6220. [PMC free article] [PubMed] 207. Mattson MP, Duan W, Wan R, Guo Z. Prophylactic activation of neuroprotective stress response pathways by dietary and behavioral manipulations. NeuroRx. 2004;1:111–116. [PMC free article] [PubMed] 208. Mattson MP. Dietary factors, hormesis and health. Ageing Res Rev. 2008;7:43–48. [PMC free article] [PubMed]

Brain-derived neurotrophic factor (BDNF), normally involved in brain development and plasticity, is elevated in IF animals, and is causally linked to the protective effect of the IF regimen against neuronal damage inflicted by the neurotoxin kainic acid [209]. 209. Duan W, Lee J, Guo Z, Mattson MP. Dietary restriction stimulates BDNF production in the brain and thereby protects neurons against excitotoxic injury. J Mol Neurosci. 2001;16:1–12. [PubMed]

Heterozygousknockout BDNF (BDNF+/-) mice exhibit metabolic abnormalities, hyperphagia, obesity, and insulin resistance that could be significantly reversed by IF, indicating that BDNF is indeed involved in the beneficial effects induced by IF [214]. 214. Duan W, Guo Z, Jiang H, Ware M, Mattson MP. Reversal of behavioral and metabolic abnormalities, and insulin resistance syndrome, by dietary restriction in mice deficient in brain-derived neurotrophic factor. Endocrinology. 2003;144:2446–2453. [PubMed]

Hormesis occurs when a low level stress elicits adaptive beneficial responses that protect against subsequent exposure to severe stress. Recent findings suggest that mild oxidative and thermal stress can extend lifespan by hormetic mechanisms. Here we show that the botanical pesticide plumbagin, while toxic to C. elegans nematodes at high doses, extends lifespan at low doses. Because plumbagin is a naphthoquinone that can generate free radicals in vivo, we investigated whether it extends lifespan by activating an adaptive cellular stress response pathway. The C. elegans cap‘n’collar (CNC) transcription factor, SKN-1, mediates protective responses to oxidative stress. Genetic analysis showed that skn-1 activity is required for lifespan extension by low-dose plumbagin in C. elegans. Further screening of a series of plumbagin analogs identified three additional naphthoquinones that could induce SKN-1 targets in C. elegans. Naphthazarin showed skn-1dependent lifespan extension, over an extended dose range compared to plumbagin, while the other naphthoquinones, oxoline and menadione, had differing effects on C. elegans survival and failed to activate ARE reporter expression in cultured mammalian cells. Our findings reveal the potential for low doses of naturally occurring naphthoquinones to extend lifespan by engaging a specific adaptive cellular stress response pathway.

Contrarily, several studies have shown that, at least at the level of individual cells, CR may slightly boost metabolic rate.

There is strong evidence that decreasing cellular metabolism is not involved in CR-induced life extension, said Edward Masoro, a professor of physiology at the University of Texas Health Science Center at San Antonio.

CR lowers glucose or sugar levels in the blood, reducing the accumulation of sugar on long-lived proteins, an effect that tends to disrupt cellular functions.

CR boosts immunological response and increases levels of protective hormones. Some scientists have noted that CR seems to work, in part, by alerting the body that food is scarce. The body responds by slowing its metabolism, boosting internal efficiencies, releasing energy stores in fat and upping the production of protective hormones that allow cells to withstand greater stress.

In roundworms, for example, starvation (or overcrowding) prompts the microscopic animals to slip into a kind of suspended animation, in effect shutting down until better times.

CR reduces mitochondrial damage. This view currently enjoys the greatest support, a fact not without some irony since the damage appears to be an unavoidable consequence of simply being alive. In every cell, there are tiny factories called mitochondria that convert raw fuel into usable energy. In the course of doing so, they produce molecules called free radicals as a by-product.

…A human study by John O. Holloszy, a professor of medicine at Washington University in St. Louis, published earlier this year noted that 18 people who had been practicing CR for three to 15 years showed dramatically reduced risk of developing diabetes or clogged arteries.

It’s very clear that calorie restriction has a powerful, protective effect against diseases associated with aging, Holloszy said. We don’t know how long each individual actually will end up living, but they certainly have a much longer life expectancy than average because they’re most likely not going to die from a heart attack, stroke or diabetes.

…Indeed, regular fasting produces at least some of the benefits of CR. The National Institute on Aging found that the time between meals might be more important than their size. Specifically, lab mice kept on an every-other-day feeding schedule with no reduction in calories boasted reduced glucose and insulin levels similar to or better than mice on CR diets.

Calorie restriction (CR) has been promoted to increase longevity. Previous studies have indicated that CR can negatively affect mood and therefore the effect of CR on mood and quality of life (QOL) becomes crucial when considering the feasibility of CR in humans. We conducted a three month clinical trial on CR (reduction of 300 to 500kcal/day) combined with two days/week of Muslim sunnah fasting (FCR) to determine the effectiveness of FCR on QOL among aging men in Klang Valley, Malaysia. A total of 25 healthy Malay men (age 58.8±5.1years), with no chronic diseases and a BMI of 23.0 to 29.9kg/m(2) were randomized to FCR (n=12) and control (n=13) groups. Body composition measurements and QOL questionnaires were ascertained at baseline, week 6 and week 12. QOL was measured using the Short-Form 36, sleep quality was determined using the Pittsburgh Sleep Quality Index, the Beck Depression Inventory II was used to measure mood and the Perceived Stress Scale was used to measure depression. The FCR group had a significant reduction in body weight, BMI, body fat percentage and depression (P<0.05). The energy component of QOL was significantly increased in FCR group (p<0.05). There were no significant changes in sleep quality and stress level between the groups as a result of the intervention., quasi IF

Honjoh et. al. established a fasting diet regimen in C. elegans to study molecular pathways involved in fasting induced longevity. They found that alternate day fasting (ADF) had a 40.4% increase in lifespan, and intermittent fasting (IF: every two days) had a 56.6% increase in lifespan over ad libitum fed worms. In contrast, chronic CR only increased lifespan by an average of 13.2%.

Dietary restriction has been shown to have several health benefits including increased insulin sensitivity, stress resistance, reduced morbidity, and increased life span. The mechanism remains unknown, but the need for a long-term reduction in caloric intake to achieve these benefits has been assumed. We report that when C57BL/6 mice are maintained on an intermittent fasting (alternate-day fasting) dietary-restriction regimen their overall food intake is not decreased and their body weight is maintained. Nevertheless, intermittent fasting resulted in beneficial effects that met or exceeded those of caloric restriction including reduced serum glucose and insulin levels and increased resistance of neurons in the brain to excitotoxic stress. Intermittent fasting therefore has beneficial effects on glucose regulation and neuronal resistance to injury in these mice that are independent of caloric intake.

CR in general:

The fat strain, known as C57BL/6, roughly doubles in weight over its adult life. That strain benefited from caloric restriction, Sohal said. The lean strain, DBA/2, does not become obese. Caloric restriction did not extend the life of these mice, confirming previous work by Forster and Sohal.

Most experimental evidence in favor of the free radical theory of ageing comes from invertebrates. In a study by Schriner et al.,[9] it was observed that mice with extra catalase in their mitochondria lived 18% more than controls and were less likely to develop cataracts, but they did not appear to age slower. The free radical theory appears to be one of the most promising explanations for the process of ageing. But, numerous experiments have shown contrasting results. Also, the prime cause for opposition to this theory arises from the fact that antioxidant supplementation has not shown to decelerate ageing.

Ageing and its implications

TODO: Warrior Diet, Ori Hofmekler Eat Stop Eat, Brad Pilon (ebook?)


IF review article: IF only works as covert CR?

Qualitatively, it worked. Shifting the last age of reproduction, which is when Hamilton’s force of natural selection acting on mortality itself plateaus, produces the qualitatively predictable shift in observed mortality plateaus in our fruit fly experiments. Not immediately, as a physiological effect, but eventually, over many generations, as a result of evolution occurring in my laboratory under controlled conditions.

Not only is the rate of aging, considered demographically, readily tuned by evolution, so is the age at which aging stops demographically readily tuned by evolution. And this is true not only of those aspects of aging that affect survival. It is also true of reproductive aging, the main theme of the doctoral research of Cassie Rauser in my laboratory. Reproductive aging is tuned by Hamilton’s other force of natural selection, the one that tunes age-specific fecundity.

…Consider the following point. If aging is a physiological process, however multifarious, why should it come to a halt just when the organism is most debilitated? In the human case, demographic aging stops when the death rate is between 30 and 50 % per year, particularly among centenarians. These are very frail people, yet their aging abruptly stops. How is this supposed to make sense?

Instead, imagine an entirely different view. Suppose instead that aging only seems like a physiological process, but actually is no such thing. Suppose instead that aging is the age-dependent tuning of Darwinian adaptation, where the tuning is determined by the patterns of Hamilton’s forces of natural selection. Not a physiological process at all.

…If this view is correct, then those species in which Hamilton’s forces of natural selection do NOT fall should be free of aging. Even if they have the same basic cell biology as we do, and even if they are as subject to mechanical injury and oxidation as we are. This alternative view thus makes some strong predictions, predictions which are readily falsified by comparative data. IF, a big if, this theory is wrong.

And the comparative data show that such species DO indeed exist. For example, sea anemones that reproduce only by symmetrical fission are animal species that are thought to be free of aging, from experiments culturing them in aquaria. Similar results have been found among other fissile coelenterates, particularly in the work of Daniel Martinez. And Graham Bell has found results like these in flatworms that can also reproduce by splitting in two. So, not only can aging stop, sometimes it doesn’t even get started.

…But I kept on thinking about the cessation of aging. In the last two years I started thinking about some data that Cassie Rauser had collected on the cessation of reproductive aging in our fruit flies. She showed that the timing of this cessation, and the reproductive function of flies that have stopped reproductive aging, depended on their environment. These findings raised the possibility, in my mind, that we might be able to manipulate when mortality declines stop too, using environmental manipulation, in fruit flies or humans.

A few fruit fly experiments later, we are already seeing signs of such an opportunity: declining and stabilizing mortality too can be manipulated environmentally. This work is by Marta Santos and her team in my lab, and will be submitted for publication soon.

The flavanol (–)-epicatechin, a component of cacao (cocoa), has been shown to have multiple health benefits in humans. Using 1-year-old male mice, we examined the effects of 15 days of (–)-epicatechin treatment and regular exercise on: (1) exercise performance, (2) muscle fatigue, (3) capillarity, and (4) mitochondrial biogenesis in mouse hindlimb and heart muscles. Twenty-five male mice (C57BL/6N) were randomized into four groups: (1) water, (2) water–exercise (W-Ex), (3) (–)-epicatechin ((–)-Epi), and (4) (–)-epicatechin–exercise ((–)-Epi-Ex). Animals received 1 mg kg−1 of (–)-epicatechin or water (vehicle) via oral gavage (twice daily). Exercise groups underwent 15 days of treadmill exercise. Significant increases in treadmill performance (∼50%) and enhanced in situ muscle fatigue resistance (∼30%) were observed with (–)-epicatechin. Components of oxidative phosphorylation complexes, mitofilin, porin, nNOS, p-nNOS, and Tfam as well as mitochondrial volume and cristae abundance were significantly higher with (–)-epicatechin treatment for hindlimb and cardiac muscles than exercise alone. In addition, there were significant increases in skeletal muscle capillarity. The combination of (–)-epicatechin and exercise resulted in further increases in oxidative phosphorylation-complex proteins, mitofilin, porin and capillarity than (–)-epicatechin alone. These findings indicate that (–)-epicatechin alone or in combination with exercise induces an integrated response that includes structural and metabolic changes in skeletal and cardiac muscles resulting in greater endurance capacity. These results, therefore, warrant the further evaluation of the underlying mechanism of action of (–)-epicatechin and its potential clinical application as an exercise mimetic.

A study was designed to determine if overweight asthma patients would adhere to an alternate day calorie restriction (ADCR) dietary regimen, and to establish the effects of the diet on their symptoms, pulmonary function and markers of oxidative stress, and inflammation. Ten subjects with BMI > 30 were maintained for 8 weeks on a dietary regimen in which they ate ad libitum every other day, while consuming less than 20% of their normal calorie intake on the intervening days. At baseline, and at designated time points during the 8-week study, asthma control, symptoms, and Quality of Life questionnaires (ACQ, ASUI, mini-AQLQ) were assessed and blood was collected for analyses of markers of general health, oxidative stress, and inflammation. Peak expiratory flow (PEF) was measured daily on awakening. Pre-and postbronchodilator spirometry was obtained at baseline and 8 weeks. Nine of the subjects adhered to the diet and lost an average of 8% of their initial weight during the study. Their asthma-related symptoms, control, and QOL improved significantly, and PEF increased significantly, within 2 weeks of diet initiation; these changes persisted for the duration of the study. Spirometery was unaffected by ADCR. Levels of serum β-hydroxybutyrate were increased and levels of leptin were decreased on CR days, indicating a shift in energy metabolism toward utilization of fatty acids and confirming compliance with the diet. The improved clinical findings were associated with decreased levels of serum cholesterol and triglycerides, striking reductions in markers of oxidative stress (8-isoprostane, nitrotyrosine, protein carbonyls, and 4-hydroxynonenal adducts), and increased levels of the antioxidant uric acid. Indicators of inflammation, including serum tumor necrosis factor-α and brain-derived neurotrophic factor, were also significantly decreased by ADCR. Compliance with the ADCR diet was high, symptoms and pulmonary function improved, and oxidative stress and inflammation declined in response to the dietary intervention.

Alternate day calorie restriction improves clinical findings and reduces markers of oxidative stress and inflammation in overweight adults with moderate asthma, Johnson et al 2006

Mattson, M. P. The need for controlled studies of the effects of meal frequency on health. Lancet 365:1978–1980; 2005

Johnson, J. B.; Laub, D. R.; John, S. The effect on health of alternate day calorie restriction: eating less and more than needed on alternate days prolongs life. Med. Hypotheses 67 (2):209–211; 2006. (covers 1956 Madrid experiment)

Bhutani S, Klempel MC, Berger RA, Varady KA. Improvements in Coronary Heart Disease Risk Indicators by Alternate-Day Fasting Involve Adipose Tissue Modulations. Obesity (Silver Spring). 2010 Mar 18. PMID 20300080.

Johnson JB, John S, Laub DR. Pretreatment with alternate day modified fast will permit higher dose and frequency of cancer chemotherapy and better cure rates. Med Hypotheses. 2009 Apr;72(4):381-82. PMID 19135806.

Heilbronn’s team put non-obese men and women on an ADF for a total of 22 days [29]. Subjects lost an average of 2.1 kg total bodyweight despite instructions to eat double their typical day’s intake every other day. Men maintained normal glucose metabolism and improved insulin response. Impaired glucose tolerance occurred in women by the end of the trial. Although a trend toward increases in resistance to stress occurred in the study, both men and women showed no changes in gene expression involved with fatty acid oxidation.

Heilbronn, et al. Glucose Tolerance and Skeletal Muscle Gene Expression in Response to Alternate Day Fasting. Obes Res. 2005 Mar;13(3):574-81.

In another 22-day ADF study led by Heilbronn, non-obese subjects lost an average of 2.5% of initial bodyweight [18]. Beneficial effects of ADF included a decrease in fasting insulin levels and respiratory quotient, indicating an average fat oxidation increase of roughly 15g per day. Unfortunately, there was an increase in hunger on the first fasting day, a condition that remained elevated for the duration of the trial.

Heilbronn, et al. Alternate-day fasting in nonobese subjects: effects on body weight, body composition, and energy metabolism. Am J Clin Nutr. 2005 Jan;81(1):69-73.

Halberg’s team examined the effect of an ADF for a total of 14 days on non-obese young men [30], and observed an increase in insulin sensitivity. In contrast to the previously discussed study, no change in bodyweight or bodyfat occurred. As a result of the ADF, insulin sensitivity and glucose uptake in muscle increased. However, there was also an increased sensitivity, or uptake-readiness in the fat cells, evidenced by an inhibition of insulin-mediated adipose tissue lipolysis. The next study we’ll examine deserves its own section, but not for the reasons you might expect.

Halberg, et al. Effect of intermittent fasting and refeeding on insulin action in healthy men. J Appl Phsiol. 2005 Dec;99(6):2128-36. Epub 2005 Jul 28.

Failure to recognize that many standard control rats and mice used in biomedical research are sedentary, obese, glucose intolerant, and on a trajectory to premature death may confound data interpretation and outcomes of human studies. Fundamental aspects of cellular physiology, vulnerability to oxidative stress, inflammation, and associated diseases are among the many biological processes affected by dietary energy intake and exercise. Although overfed sedentary rodents may be reasonable models for the study of obesity in humans, treatments shown to be efficacious in these animal models may prove ineffective or exhibit novel side effects in active, normal-weight subjects.

Control" laboratory rodents are metabolically morbid: Why it matters“

Dietary restriction has been shown to have several health benefits including increased insulin sensitivity, stress resistance, reduced morbidity, and increased life span. The mechanism remains unknown, but the need for a long-term reduction in caloric intake to achieve these benefits has been assumed. We report that when C57BL/6 mice are maintained on an intermittent fasting (alternate-day fasting) dietary-restriction regimen their overall food intake is not decreased and their body weight is maintained. Nevertheless, intermittent fasting resulted in beneficial effects that met or exceeded those of caloric restriction including reduced serum glucose and insulin levels and increased resistance of neurons in the brain to excitotoxic stress. Intermittent fasting therefore has beneficial effects on glucose regulation and neuronal resistance to injury in these mice that are independent of caloric intake.

Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from calorie intake

A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan

The Effects of Intermittent Energy Restriction on Indices of Cardiometabolic Health, Antoni et al 2014

The effects of intermittent fasting on human and animal health: a systematic review, Kostevski 2012

A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan, Brandhorst 2015

Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease, Wei et al 2017

Effect of Alternate-Day Fasting on Weight Loss, Weight Maintenance, and Cardioprotection Among Metabolically Healthy Obese Adults: A Randomized Clinical Trial, Trepanowski et al 2017:

Importance: Alternate-day fasting has become increasingly popular, yet, to date, no long-term randomized clinical trials have evaluated its efficacy.

Objective: To compare the effects of alternate-day fasting vs daily calorie restriction on weight loss, weight maintenance, and risk indicators for cardiovascular disease.

Design, Setting, and Participants: A single-center randomized clinical trial of obese adults (18 to 64 years of age; mean body mass index, 34) was conducted between October 1, 2011, and January 15, 2015, at an academic institution in Chicago, Illinois.

Interventions: Participants were randomized to 1 of 3 groups for 1 year: alternate-day fasting (25% of energy needs on fast days; 125% of energy needs on alternating feast days), calorie restriction (75% of energy needs every day), or a no-intervention control. The trial involved a 6-month weight-loss phase followed by a 6-month weight-maintenance phase.

Main Outcomes and Measures: The primary outcome was change in body weight. Secondary outcomes were adherence to the dietary intervention and risk indicators for cardiovascular disease.

Results: Among the 100 participants (86 women and 14 men; mean [SD] age, 44 [11] years), the dropout rate was highest in the alternate-day fasting group (13 of 34 [38%]), vs the daily calorie restriction group (10 of 35 [29%]) and control group (8 of 31 [26%]). Mean weight loss was similar for participants in the alternate-day fasting group and those in the daily calorie restriction group at month 6 (–6.8% [95% CI, –9.1% to –4.5%] vs –6.8% [95% CI, –9.1% to –4.6%]) and month 12 (–6.0% [95% CI, –8.5% to –3.6%] vs –5.3% [95% CI, –7.6% to –3.0%]) relative to those in the control group. Participants in the alternate-day fasting group ate more than prescribed on fast days, and less than prescribed on feast days, while those in the daily calorie restriction group generally met their prescribed energy goals. There were no significant differences between the intervention groups in blood pressure, heart rate, triglycerides, fasting glucose, fasting insulin, insulin resistance, C-reactive protein, or homocysteine concentrations at month 6 or 12. Mean high-density lipoprotein cholesterol levels at month 6 significantly increased among the participants in the alternate-day fasting group (6.2 mg/dL [95% CI, 0.1-12.4 mg/dL]), but not at month 12 (1.0 mg/dL [95% CI, –5.9 to 7.8 mg/dL]), relative to those in the daily calorie restriction group. Mean low-density lipoprotein cholesterol levels were significantly elevated by month 12 among the participants in the alternate-day fasting group (11.5 mg/dL [95% CI, 1.9-21.1 mg/dL]) compared with those in the daily calorie restriction group.

Conclusions and Relevance: Alternate-day fasting did not produce superior adherence, weight loss, weight maintenance, or cardioprotection vs daily calorie restriction.