Intermittent fasting for obesity and related disorders: unveiling myths, facts, and presumptions

Bruno Halpern Thiago Bosco Mendes About the authors

ABSTRACT

Intermittent fasting (IF) is an increasingly popular method of weight loss, as an alternative to daily caloric restriction (DCR). Several forms of IF exist, such as alternate-day fasting or time-restricted feeding regimens. Some of its proponents claim several health benefits unrelated to caloric restriction or weight loss, which rely mainly on animal models. Although several studies published in the last few years confirm that IF can be a useful and safe therapeutical option for obesity and related disorders, no superiority to conventional caloric restriction diets have emerged. There are still several questions left answered. In this Review, we discuss some of the claims, unveiling myths, facts, and presumptions about several models of IF. The focus of this article is obesity, but there is a brief discussion of the potential benefits of IF on overall human health.

Keywords
Obesity; intermittent fasting; type 2 diabetes; weight loss; diets; insulin resistance; circadian rhythm

INTRODUCTION

Intermittent fasting (IF) has received great interest from the general public, as an alternative to the traditional daily energy restriction model, for the treatment of obesity and related disorders, but also as an anti-aging method increasing longevity (11. de Cabo R, Mattson MP. Effects of Intermittent Fasting on Health, Aging, and Disease. [published correction appears in N Engl J Med. 2020 Jan 16;382(3):298] [published correction appears in N Engl J Med. 2020 Mar 5;382(10):978]. N Engl J Med. 2019;381(26):2541-51.33. Patterson RE, Sears DD. Metabolic Effects of Intermittent Fasting. Annu Rev Nutr. 2017;37:371-93.). Even though IF is a promising approach for some patients, there have been several claims of its benefits (mainly in social media) that are not evidence-based, at least in humans, leading to doubts among the society and sharp disagreements by its supporters and critics. As such, a critical appraisal of the literature is imperative to guide health professionals advising their patients, while not exaggerating its benefits, nor condemning its practice, yet also raising questions that may be answered by controlled trials in the future.

Recently, the medical community’s interest in this topic grew even further after the publication of a review article in the New England Journal of Medicine in late 2019 (11. de Cabo R, Mattson MP. Effects of Intermittent Fasting on Health, Aging, and Disease. [published correction appears in N Engl J Med. 2020 Jan 16;382(3):298] [published correction appears in N Engl J Med. 2020 Mar 5;382(10):978]. N Engl J Med. 2019;381(26):2541-51.). That review article discusses, beyond obesity, several other potential targets for therapeutic fasting, such as the treatment of neurological disease, cancer, and cardiovascular disease. However, the article should be interpreted cautiously, as the authors clearly stated that the majority of the benefits were demonstrated in animal models, with much less data from humans. Moreover, in many of the cited articles, it is difficult to differentiate whether the effect of IF is a consequence of weight loss, caloric restriction, the fasting itself, or the interaction of these factors. This present Review aims to give a perspective of the evidence regarding intermittent fasting in humans, especially in the setting of metabolic diseases.

INTERMITTENT FASTING: ONE NAME, SEVERAL PROTOCOLS

The term “Intermittent fasting” comprises several different forms of daily or weekly food intake patterns. Fasting is a common religious practice as well (44. Hoddy KK, Marlatt KL, Çetinkaya H, Ravussin E. Intermittent Fasting and Metabolic Health: From Religious Fast to Time-Restricted Feeding. Obesity (Silver Spring). 2020;28 Suppl 1(Suppl 1):S29-S37.), but religious fasting will not be discussed in this article. Each IF protocol should be analyzed by itself regarding weight loss, metabolic and inflammatory profile, anti-oxidative effects, ketone bodies production, and adherence in the mid- and long-term. Circadian rhythms should also be taken into account, as similar feeding windows in different periods of the day could have a different cardiometabolic impact (55. Wilkinson MJ, Manoogian ENC, Zadourian A, Lo H, Fakhouri S, Shoghi A, et al. Ten-Hour Time-Restricted Eating Reduces Weight, Blood Pressure, and Atherogenic Lipids in Patients with Metabolic Syndrome. Cell Metab. 2020;31(1):92-104.e5.77. Asher G, Sassone-Corsi P. Time for food: the intimate interplay between nutrition, metabolism, and the circadian clock. Cell. 2015;161(1):84-92.).

Every discussion considering different forms of fasting as having similar results is inevitably incomplete. Among the most studied IF protocols, three are summarized below and in Table 1 (33. Patterson RE, Sears DD. Metabolic Effects of Intermittent Fasting. Annu Rev Nutr. 2017;37:371-93.,44. Hoddy KK, Marlatt KL, Çetinkaya H, Ravussin E. Intermittent Fasting and Metabolic Health: From Religious Fast to Time-Restricted Feeding. Obesity (Silver Spring). 2020;28 Suppl 1(Suppl 1):S29-S37.,88. Stockman MC, Thomas D, Burke J, Apovian CM. Intermittent Fasting: Is the Wait Worth the Weight? Curr Obes Rep. 2018;7(2):172-85.):

  • Complete alternate-day fasting (ADF): involves alternating days containing no-energy food with eating ad libitum days;

  • Modified alternate-day fasting (MADF): different variations in ADF. The most popular is “intermittent fasting 5:2”: allows five days per week of ad libitum feeding and makes absolute fasting or restricts the intake to no more than 25% of the daily necessity on the other two days (11. de Cabo R, Mattson MP. Effects of Intermittent Fasting on Health, Aging, and Disease. [published correction appears in N Engl J Med. 2020 Jan 16;382(3):298] [published correction appears in N Engl J Med. 2020 Mar 5;382(10):978]. N Engl J Med. 2019;381(26):2541-51.,22. Mattson MP, Allison DB, Fontana L, Harvie M, Longo VD, Malaisse WJ, et al. Meal frequency and timing in health and disease. Proc Natl Acad Sci U S A. 2014;111(47):16647-53.). These two days can be consecutive or not consecutive;

  • “Time-restricted feeding” (TRF): allows ad libitum intake during specific times (few hours) and fasting for a prolonged time during each day. Another variation is restricting intake throughout the night, following the circadian rhythm.

Table 1
Different patterns of IF

PROPOSED MECHANISMS MAINLY BASED ON ANIMAL MODELS

Most of the proposed direct mechanisms of intermittent fasting in diseases come from animal models, in which caloric restriction has been extensively associated with increased survival in many species. However, in most of these models, the animals tend to eat within a period of a few hours, generally in the active phase of their circadian day, and they fast during the rest of the 24-hour period. As such, it has been hypothesized that many of the benefits attributed to caloric restriction itself could be related to this long fasting period (11. de Cabo R, Mattson MP. Effects of Intermittent Fasting on Health, Aging, and Disease. [published correction appears in N Engl J Med. 2020 Jan 16;382(3):298] [published correction appears in N Engl J Med. 2020 Mar 5;382(10):978]. N Engl J Med. 2019;381(26):2541-51.).

During fasting, there is a decrease in insulin levels and an increase in ketone bodies’ production, such as beta-hydroxybutyrate, a signaling metabolite that elicits several direct and indirect molecular responses (99. Newman JC, Verdin E. β-Hydroxybutyrate: A Signaling Metabolite. Annu Rev Nutr. 2017;37:51-76.). Those responses could reduce inflammation, oxidative stress, tumorigenesis, and aging (1010. Puchalska P, Crawford PA. Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics. Cell Metab. 2017;25(2):262-84.). Among those signals, fasting and ketogenesis could increase AMPK and sirtuin gene expression, reduce mTor signaling (which is associated with cellular growth and cancer), increase mitochondrial biogenesis and autophagy and reduce sympathetic tone (11. de Cabo R, Mattson MP. Effects of Intermittent Fasting on Health, Aging, and Disease. [published correction appears in N Engl J Med. 2020 Jan 16;382(3):298] [published correction appears in N Engl J Med. 2020 Mar 5;382(10):978]. N Engl J Med. 2019;381(26):2541-51.,99. Newman JC, Verdin E. β-Hydroxybutyrate: A Signaling Metabolite. Annu Rev Nutr. 2017;37:51-76.1111. Mattson MP, Longo VD, Harvie M. Impact of intermittent fasting on health and disease processes. Ageing Res Rev. 2017;39:46-58.). Autophagy, in particular, is important for the removal of damaged cells and is associated with reduced aging and increased longevity in animals models (1212. Hansen M, Rubinsztein DC, Walker DW. Autophagy as a promoter of longevity: insights from model organisms. [Erratum in: Nat Rev Mol Cell Biol. 2018]. Nat Rev Mol Cell Biol. 2018;19(9):579-93.). Indeed, many chronic diseases are associated with accumulation of dysfunctional cellular components and it is hypothesized that a shift from an anabolic post-prandial state to a catabolic state of reduced insulin is crucial for an effective autophagy to occur (11. de Cabo R, Mattson MP. Effects of Intermittent Fasting on Health, Aging, and Disease. [published correction appears in N Engl J Med. 2020 Jan 16;382(3):298] [published correction appears in N Engl J Med. 2020 Mar 5;382(10):978]. N Engl J Med. 2019;381(26):2541-51.,1212. Hansen M, Rubinsztein DC, Walker DW. Autophagy as a promoter of longevity: insights from model organisms. [Erratum in: Nat Rev Mol Cell Biol. 2018]. Nat Rev Mol Cell Biol. 2018;19(9):579-93.,1313. Russel RC, Yuan HX, Guan KL. Autophagy regulation by nutrient signaling. Cell Research 2014;24:42-57). Ketogenesis could also have an impact on epigenetic signaling by inhibiting histone deacetylases (99. Newman JC, Verdin E. β-Hydroxybutyrate: A Signaling Metabolite. Annu Rev Nutr. 2017;37:51-76.). Those mechanisms would positively have an impact on several diseases associated with inflammation, aging, and cellular growth, such as cancer, cardiovascular disease, type 2 diabetes, dementia, and auto-immune diseases (11. de Cabo R, Mattson MP. Effects of Intermittent Fasting on Health, Aging, and Disease. [published correction appears in N Engl J Med. 2020 Jan 16;382(3):298] [published correction appears in N Engl J Med. 2020 Mar 5;382(10):978]. N Engl J Med. 2019;381(26):2541-51.,1111. Mattson MP, Longo VD, Harvie M. Impact of intermittent fasting on health and disease processes. Ageing Res Rev. 2017;39:46-58.). More immediate effects of ketone bodies’ production are enhanced lipolysis, reduced hunger, and improved mental and physical performance (including improved running endurance), which could influence the treatment of obesity (11. de Cabo R, Mattson MP. Effects of Intermittent Fasting on Health, Aging, and Disease. [published correction appears in N Engl J Med. 2020 Jan 16;382(3):298] [published correction appears in N Engl J Med. 2020 Mar 5;382(10):978]. N Engl J Med. 2019;381(26):2541-51.,1414. Deemer SE, Plaisance EP, Martins C. Impact of ketosis on appetite regulation-a review. Nutr Res. 2020;77:1-11.). Interestingly, central infusion of ketone bodies potentiated leptin and insulin brain signaling (possibly affecting food intake) and directly improved hepatic insulin sensitivity, suggesting effects on insulin resistance, independent of weight loss (1515. Park S, Kim DS, Daily JW. Central infusion of ketone bodies modulates body weight and hepatic insulin sensitivity by modifying hypothalamic leptin and insulin signaling pathways in type 2 diabetic rats. Brain Res. 2011;1401:95-103.). This direct effect of ketones on whole body insulin disposal has been shown in other animal models, as well (1111. Mattson MP, Longo VD, Harvie M. Impact of intermittent fasting on health and disease processes. Ageing Res Rev. 2017;39:46-58.,1616. Anson RM, Guo Z, de Cabo R, Iyun T, Rios M, Hagepanos A, et al. 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(10):6216-20.). Ketones can also have a protein-sparing effect in obesity by inhibiting oxidation of branched chain amino acids, mainly alanine, in muscle (1717. Thomas DD, Istfan NW, Bistrian BR, Apovian CM. Protein sparing therapies in acute illness and obesity: a review of George Blackburn’s contributions to nutrition science. Metabolism. 2018;79:83-96.). Nonetheless, studies performed decades ago observed that this protein sparing effect is dependent on the initial weight of participants, and individuals without obesity have increased loss of muscle mass during ketosis (1717. Thomas DD, Istfan NW, Bistrian BR, Apovian CM. Protein sparing therapies in acute illness and obesity: a review of George Blackburn’s contributions to nutrition science. Metabolism. 2018;79:83-96.1919. Van Itallie TB, Yang MU. Current concepts in nutrition: diet and weight loss. N Engl J Med. 1977;297:1158-61.).

It has been proposed that living species should have mechanisms to adapt to long periods of food deprivation, with a clear metabolic switch from a fed to fasted state, occurring several times a week. In this context, the standard human pattern of three big meals a day, plus snacking, could be maladaptive, maintaining humans in a constant anabolic post-prandial state of increased insulin levels and no ketone bodies’ production (1111. Mattson MP, Longo VD, Harvie M. Impact of intermittent fasting on health and disease processes. Ageing Res Rev. 2017;39:46-58.).

A couple of published reviews have deeply discussed several of the above-mentioned molecular mechanisms (11. de Cabo R, Mattson MP. Effects of Intermittent Fasting on Health, Aging, and Disease. [published correction appears in N Engl J Med. 2020 Jan 16;382(3):298] [published correction appears in N Engl J Med. 2020 Mar 5;382(10):978]. N Engl J Med. 2019;381(26):2541-51.33. Patterson RE, Sears DD. Metabolic Effects of Intermittent Fasting. Annu Rev Nutr. 2017;37:371-93.,99. Newman JC, Verdin E. β-Hydroxybutyrate: A Signaling Metabolite. Annu Rev Nutr. 2017;37:51-76.,1111. Mattson MP, Longo VD, Harvie M. Impact of intermittent fasting on health and disease processes. Ageing Res Rev. 2017;39:46-58.), and we will focus this manuscript on human data from this point on.

INTERMITTENT FASTING FOR TREATING OBESITY: IS IT SUPERIOR TO DAILY CALORIC RESTRICTION?

Many IF advocates claim in social media and books that this strategy increases energetic expenditure, leading to higher weight loss than daily caloric restriction (2020. Fung J. The Obesity Code: unlocking the secrets of weight loss. Vancouver: Greystone Books; 2016.). The theory defended by supporters is that part of its effect is secondary to a reduction in insulin levels (2121. Ludwig DS, Ebbeling CB. The Carbohydrate-Insulin Model of Obesity: Beyond “Calories In, Calories Out”. JAMA Intern Med. 2018;178(8):1098-103.), due to the carbohydrate-insulin model. This model states that hyperinsulinemia (elicited by excessive carbohydrate intake, mainly those with higher glycemic index) causes obesity by trapping metabolic fuels inside the adipose tissue. Consequently, eating would lead to a reduction in energy bioavailability to other tissues, including the brain, which, in turn, would interpret that the body is under an energy deficit, then adapting through increased hunger and reduced energy expenditure (2121. Ludwig DS, Ebbeling CB. The Carbohydrate-Insulin Model of Obesity: Beyond “Calories In, Calories Out”. JAMA Intern Med. 2018;178(8):1098-103.). Overall, this theory considers that the increased food intake and decreased energy expenditure are consequences, not causes, of obesity. Currently, although some authors still defend it (2121. Ludwig DS, Ebbeling CB. The Carbohydrate-Insulin Model of Obesity: Beyond “Calories In, Calories Out”. JAMA Intern Med. 2018;178(8):1098-103.,2222. Ludwig DS, Ebbeling CB, Bikman BT, Johnson JD. Testing the carbohydrate-insulin model in mice: The importance of distinguishing primary hyperinsulinemia from insulin resistance and metabolic dysfunction. Mol Metab. 2020;35:100960.), this theory has been widely discredited by experimental models in animals and humans (2323. Hall KD. A review of the carbohydrate-insulin model of obesity [published correction appears in Eur J Clin Nutr. 2017 May;71(5):679]. Eur J Clin Nutr. 2017;71(3):323-6.2525. Hu S, Wang L, Togo J, Yang D, Xu Y, Wu Y, et al. The carbohydrate-insulin model does not explain the impact of varying dietary macronutrients on the body weight and adiposity of mice. Mol Metab. 2020;32:27-43.). Also, isocaloric studies performed in metabolic chambers demonstrate that the differences in weight loss and energy expenditure among different macronutrients are clinically negligible (2626. Hall KD, Guo J, Speakman JR. Do low-carbohydrate diets increase energy expenditure? Int J Obes (Lond). 2019;43(12):2350-4.2828. Hall KD, Bemis T, Brychta R, Chen KY, Courville A, Crayner EJ, et al. Calorie for Calorie, Dietary Fat Restriction Results in More Body Fat Loss than Carbohydrate Restriction in People with Obesity. Cell Metab. 2015;22(3):427-36.). Although these studies did not evaluate fasting itself, but the differences between low-carb and low-fat diets, they reject the hypothesis that high insulin is, by itself, a major driver of weight gain in humans. Another study in a metabolic chamber evaluated time-restricted feeding (18 hours fasting) against 12 hours fasting in an isocaloric setting, and showed no difference in the weight loss between both groups (though there were differences in metabolic parameters, that are going to be discussed further ahead) (66. Sutton EF, Beyl R, Early KS, Cefalu WT, Ravussin E, Peterson CM. Early Time-Restricted Feeding Improves Insulin Sensitivity, Blood Pressure, and Oxidative Stress Even without Weight Loss in Men with Prediabetes. Cell Metab. 2018;27(6):1212-21.e3.). Other theoretical benefits on obesity treatment from intermittent fasting are the suppression of appetite (favoring caloric deficit), the improvement of physical disposition, and the improvement of metabolic parameters (22. Mattson MP, Allison DB, Fontana L, Harvie M, Longo VD, Malaisse WJ, et al. Meal frequency and timing in health and disease. Proc Natl Acad Sci U S A. 2014;111(47):16647-53.,44. Hoddy KK, Marlatt KL, Çetinkaya H, Ravussin E. Intermittent Fasting and Metabolic Health: From Religious Fast to Time-Restricted Feeding. Obesity (Silver Spring). 2020;28 Suppl 1(Suppl 1):S29-S37.). As stated before, some of those mechanisms are related to increased ketogenesis. However, the increase in ketone bodies are different between different IF patterns, being higher in the fasting day of ADF, and probably mild in TRF models (1111. Mattson MP, Longo VD, Harvie M. Impact of intermittent fasting on health and disease processes. Ageing Res Rev. 2017;39:46-58.,2929. Johnson JB, Summer W, Cutler RG, Martin B, Hyun DH, Dixit VD, et al. Alternate day calorie restriction improves clinical findings and reduces markers of oxidative stress and inflammation in overweight adults with moderate asthma. [Erratum in: Free Radic Biol Med. 2007 Nov 1;43(9):1348. Tellejohan, Richard (corrected to Telljohann, Richard). Free Radic Biol Med. 2007;42(5):665-74.). Whether those increases could mimic the benefits of animal models of IF, in which larger ketone bodies production occurs, is uncertain. Interestingly, however, a study performing MADF (20% caloric intake on fasting days, alternate with ad libitum food intake every other day) in 10 individuals with asthma have shown, after 8 weeks, that even on ad libitum days, beta-hydroxybutyrate levels were significantly higher than in the baseline (2929. Johnson JB, Summer W, Cutler RG, Martin B, Hyun DH, Dixit VD, et al. Alternate day calorie restriction improves clinical findings and reduces markers of oxidative stress and inflammation in overweight adults with moderate asthma. [Erratum in: Free Radic Biol Med. 2007 Nov 1;43(9):1348. Tellejohan, Richard (corrected to Telljohann, Richard). Free Radic Biol Med. 2007;42(5):665-74.).

A systematic review searching for human trials published from January 1, 2000 to July 1, 2019 focusing on IF for weight loss, found only 18 small RCTs and 9 trials without active controls (3030. Welton S, Minty R, O’Driscoll T, Willms H, Poirier D, Madden S, et al. Intermittent fasting and weight loss: Systematic review. Can Fam Physician. 2020;66(2):117-25.). In this study, the average reduction in body mass index was 4.3%, with weight losses ranging from 0.8% to 13%, and a high grade of heterogeneity. Still, it concluded that it was not possible to directly compare IF with other strategies of caloric restriction. Some of the most relevant studies will be discussed below.

Alternate-fasting (ADF) and modified alternate-day fasting regimens (MADF) are the most studied methods of IF to date. There are many studies with several different feeding and fasting protocols, such as the 5:2 and 3 or 4 days of energy restriction (Table 1). Short-term trials tend to show better results with IF (as adherence is higher), even though results are mixed (3030. Welton S, Minty R, O’Driscoll T, Willms H, Poirier D, Madden S, et al. Intermittent fasting and weight loss: Systematic review. Can Fam Physician. 2020;66(2):117-25.). For instance, a study of 115 overweight women showed a higher fat mass loss in the group with MADF (2 days per week with 30% of the daily caloric needs) when compared to daily caloric restriction (75% of the daily caloric necessity); however, total weight, central adiposity, and hunger scores did not differ between the groups (3131. Harvie M, Wright C, Pegington M, McMullan D, Mitchell E, Martin B, et al. The effect of intermittent energy and carbohydrate restriction v. daily energy restriction on weight loss and metabolic disease risk markers in overweight women. Br J Nutr. 2013;110(8):1534-47.). Nonetheless, some studies show increased hunger in the first days of the 5:2 regimens and reduced hunger afterwards, but results are equivocal, and the overall evidence is not conclusive (44. Hoddy KK, Marlatt KL, Çetinkaya H, Ravussin E. Intermittent Fasting and Metabolic Health: From Religious Fast to Time-Restricted Feeding. Obesity (Silver Spring). 2020;28 Suppl 1(Suppl 1):S29-S37.,3232. Harvey J, Howell A, Morris J, Harvie M. Intermittent energy restriction for weight loss: Spontaneous reduction of energy intake on unrestricted days. Food Sci Nutr. 2018;6(3):674-80.).

Trepanowski and cols. published a landmark study regarding obesity and MADF in 2017 (3333. Trepanowski JF, Kroeger CM, Barnosky A, Klempel MC, Bhutani S, Hoddy KK, et al. Effect of Alternate-Day Fasting on Weight Loss, Weight Maintenance, and Cardioprotection Among Metabolically Healthy Obese Adults: A Randomized Clinical Trial. JAMA Intern Med. 2017;177(7):930-8.). In this randomized controlled trial (RCT), 100 obese adults were assigned to 3 arms in a 6-month weight-loss phase, followed by a 6-month weight-maintenance period: alternate-day fasting (25% of energy needs on a fasting day, 125% of energy needs on the other day), calorie restriction (75% of energy needs every day), or no-intervention (control). The weight loss was higher in both the calorie restriction and IF group compared to control (mean of 6.8%) with no differences in the inflammatory and cardiovascular risk markers. However, a post-hoc analysis suggested that intermittent fasting provided increased insulin sensitivity among patients with previous insulin resistance (3434. Gabel K, Kroeger CM, Trepanowski JF, Hoddy KK, Cienfuegos S, Kalam F, et al. Differential Effects of Alternate-Day Fasting Versus Daily Calorie Restriction on Insulin Resistance. Obesity (Silver Spring). 2019;27(9):1443-50.). Interestingly, throughout the study, IF patients began to eat more calories on the restriction day and less on the “feast days,” approaching the standard diet, and the drop-out rate was higher in the IF group (38% vs. 29%). These findings clearly evidenced that a significant limitation of IF is adherence in the mid- and long-term (88. Stockman MC, Thomas D, Burke J, Apovian CM. Intermittent Fasting: Is the Wait Worth the Weight? Curr Obes Rep. 2018;7(2):172-85.,3333. Trepanowski JF, Kroeger CM, Barnosky A, Klempel MC, Bhutani S, Hoddy KK, et al. Effect of Alternate-Day Fasting on Weight Loss, Weight Maintenance, and Cardioprotection Among Metabolically Healthy Obese Adults: A Randomized Clinical Trial. JAMA Intern Med. 2017;177(7):930-8.).

Two other studies with different protocols and a one-year duration showed no difference between daily caloric restriction and IF, not only in weight, but also in markers such as glycated hemoglobin. Importantly, one of the studies was performed in patients with type 2 diabetes (3535. Headland ML, Clifton PM, Keogh JB. Effect of intermittent compared to continuous energy restriction on weight loss and weight maintenance after 12 months in healthy overweight or obese adults [published correction appears in Int J Obes (Lond). 2019 Apr;43(4):942]. Int J Obes (Lond). 2019;43(10):2028-36.,3636. Carter S, Clifton PM, Keogh JB. Effect of Intermittent Compared With Continuous Energy Restricted Diet on Glycemic Control in Patients With Type 2 Diabetes: A Randomized Noninferiority Trial. JAMA Netw Open. 2018;1(3):e180756.). In this way, medium- and long-term studies’ trials failed to show a superior benefit in weight loss from IF compared to traditional daily caloric restriction. However, this does not mean that it is a fad strategy. Recent studies are focusing on identifying good-responders (44. Hoddy KK, Marlatt KL, Çetinkaya H, Ravussin E. Intermittent Fasting and Metabolic Health: From Religious Fast to Time-Restricted Feeding. Obesity (Silver Spring). 2020;28 Suppl 1(Suppl 1):S29-S37.,3737. Kroeger CM, Trepanowski JF, Klempel MC, Barnosky A, Bhutani S, Gabel K, et al. Eating behavior traits of successful weight losers during 12 months of alternate-day fasting: An exploratory analysis of a randomized controlled trial. Nutr Health. 2018;24(1):5-10.,3838. Heilbronn LK, Smith SR, Martin CK, Anton SD, Ravussin E. Alternate-day fasting in nonobese subjects: effects on body weight, body composition, and energy metabolism. Am J Clin Nutr. 2005;81(1):69-73.). For instance, a post-hoc exploratory analysis of the trial performed by Trepanowski and cols., described above, assessed those “good-responder” patients, defined as those who lost more than 5% of their total body weight; regardless of the arm they were assigned. No differences were found regarding appetite and food intake behavior between the different diets groups in those “good responders” (3737. Kroeger CM, Trepanowski JF, Klempel MC, Barnosky A, Bhutani S, Gabel K, et al. Eating behavior traits of successful weight losers during 12 months of alternate-day fasting: An exploratory analysis of a randomized controlled trial. Nutr Health. 2018;24(1):5-10.). However, some propose that “big eaters” would benefit less from MADF, as they can more easily overconsume on the days of regular feeding (44. Hoddy KK, Marlatt KL, Çetinkaya H, Ravussin E. Intermittent Fasting and Metabolic Health: From Religious Fast to Time-Restricted Feeding. Obesity (Silver Spring). 2020;28 Suppl 1(Suppl 1):S29-S37.,3838. Heilbronn LK, Smith SR, Martin CK, Anton SD, Ravussin E. Alternate-day fasting in nonobese subjects: effects on body weight, body composition, and energy metabolism. Am J Clin Nutr. 2005;81(1):69-73.).

Fewer studies exist with complete ADF (total fasting on designated days). A recent one, in non-obese subjects, showed that four weeks of ADF led to a body weight reduction of 4.5% and an improvement in several cardiometabolic parameters, reduced visceral fat, increased polyunsaturated fatty acids levels (PUFAs), and reduced T3 levels (3939. Stekovic S, Hofer SJ, Tripolt N, Aon MA, Royer P, Pein L, et al. Alternate Day Fasting Improves Physiological and Molecular Markers of Aging in Healthy, Non-obese Humans [published correction appears in Cell Metab. 2020 Apr 7;31(4):878-881]. Cell Metab. 2019;30(3):462-76.e6.). These results are similar to several models of caloric restriction and IF in animals (11. de Cabo R, Mattson MP. Effects of Intermittent Fasting on Health, Aging, and Disease. [published correction appears in N Engl J Med. 2020 Jan 16;382(3):298] [published correction appears in N Engl J Med. 2020 Mar 5;382(10):978]. N Engl J Med. 2019;381(26):2541-51.,4040. Rubinsztein DC, Mariño G, Kroemer G. Autophagy and aging. Cell. 2011;146(5):682-95.,4141. Madeo F, Carmona-Gutierrez D, Hofer SJ, Kroemer G. Caloric Restriction Mimetics against Age-Associated Disease: Targets, Mechanisms, and Therapeutic Potential. Cell Metab. 2019;29(3):592-610.). However, it lacks a control group with the same weight loss to evaluate weight-independent mechanisms of IF. Despite the controversy of the efficacy, it is essential to highlight that MADF and ADF are generally safe (11. de Cabo R, Mattson MP. Effects of Intermittent Fasting on Health, Aging, and Disease. [published correction appears in N Engl J Med. 2020 Jan 16;382(3):298] [published correction appears in N Engl J Med. 2020 Mar 5;382(10):978]. N Engl J Med. 2019;381(26):2541-51.,22. Mattson MP, Allison DB, Fontana L, Harvie M, Longo VD, Malaisse WJ, et al. Meal frequency and timing in health and disease. Proc Natl Acad Sci U S A. 2014;111(47):16647-53.,44. Hoddy KK, Marlatt KL, Çetinkaya H, Ravussin E. Intermittent Fasting and Metabolic Health: From Religious Fast to Time-Restricted Feeding. Obesity (Silver Spring). 2020;28 Suppl 1(Suppl 1):S29-S37.,3939. Stekovic S, Hofer SJ, Tripolt N, Aon MA, Royer P, Pein L, et al. Alternate Day Fasting Improves Physiological and Molecular Markers of Aging in Healthy, Non-obese Humans [published correction appears in Cell Metab. 2020 Apr 7;31(4):878-881]. Cell Metab. 2019;30(3):462-76.e6.), with no reports of severe adverse effects. Metabolic adaptation after weight loss, an important obstacle for long-term weight maintenance, appears to be similar to DCR (4242. Coutinho SR, Halset EH, Gåsbakk S, Rehfeld JF, Kulseng B, Truby H, et al. Compensatory mechanisms activated with intermittent energy restriction: A randomized control trial. Clin Nutr. 2018;37(3):815-23.). IF does not increase the risk of an eating disorder (ED) (4343. Hoddy KK, Kroeger CM, Trepanowski JF, Barnosky AR, Bhutani S, Varady KA. Safety of alternate day fasting and effect on disordered eating behaviors. Nutr J. 2015;14:44.), but it should not be indicated for patients with ED, as studies excluded these patients. There is a risk that proposing IF for these individuals can be mistakenly used to validate a chaotic eating pattern of restriction and indulgence.

“Time-restricted feeding” (TRF) trials are being published only in the last few years, yet it is probably the most popular type of IF in clinical practice. Defenders of this principle, base their arguments on the already mentioned animal models, in which over 16 hours of fasting per day improves metabolic markers and brings neuroprotection, which could be explained, at least partially, by an increase in ketone bodies (22. Mattson MP, Allison DB, Fontana L, Harvie M, Longo VD, Malaisse WJ, et al. Meal frequency and timing in health and disease. Proc Natl Acad Sci U S A. 2014;111(47):16647-53.). In humans, however, there is evidence that these same 16 hours just discretely increase ketone bodies, preventing any definitive conclusions on the overall benefit of this strategy without dedicated studies. (11. de Cabo R, Mattson MP. Effects of Intermittent Fasting on Health, Aging, and Disease. [published correction appears in N Engl J Med. 2020 Jan 16;382(3):298] [published correction appears in N Engl J Med. 2020 Mar 5;382(10):978]. N Engl J Med. 2019;381(26):2541-51.,22. Mattson MP, Allison DB, Fontana L, Harvie M, Longo VD, Malaisse WJ, et al. Meal frequency and timing in health and disease. Proc Natl Acad Sci U S A. 2014;111(47):16647-53.,4444. Cahill GF Jr. Starvation in man. N Engl J Med. 1970;282(12):668-75.,4545. Longo VD, Mattson MP. Fasting: molecular mechanisms and clinical applications. Cell Metab. 2014;19(2):181-92.).

Wilkinson and cols. performed a trial in which individuals who had a mean eating interval of 15.13 hours per day, reduced it to a mean of 10.78 h for 12 weeks (55. Wilkinson MJ, Manoogian ENC, Zadourian A, Lo H, Fakhouri S, Shoghi A, et al. Ten-Hour Time-Restricted Eating Reduces Weight, Blood Pressure, and Atherogenic Lipids in Patients with Metabolic Syndrome. Cell Metab. 2020;31(1):92-104.e5.). The individuals’ baseline status was used as the control, and the results showed a mean of 3.3 kg weight loss and a decrease in fat mass, LDL-cholesterol and non-HDL-cholesterol, blood pressure, and alterations of other metabolic factors. This was a single-arm study, and though mixed linear models suggested that metabolic improvements were not attributed to changes in weight, the lack of a control arm prevents a definite conclusion (55. Wilkinson MJ, Manoogian ENC, Zadourian A, Lo H, Fakhouri S, Shoghi A, et al. Ten-Hour Time-Restricted Eating Reduces Weight, Blood Pressure, and Atherogenic Lipids in Patients with Metabolic Syndrome. Cell Metab. 2020;31(1):92-104.e5.).

One pilot study involving 23 patients with obesity, compared to a historical control group, observed a 2.6% weight reduction with an 8-hour window from 10:00-18:00, without calorie counting, and a reduction in blood pressure (4646. Gabel K, Hoddy KK, Haggerty N, Song J, Kroeger CM, Trepanowski JF, et al. Effects of 8-hour time restricted feeding on body weight and metabolic disease risk factors in obese adults: A pilot study. Nutr Healthy Aging. 2018;4(4):345-53.). Recently, however, a larger RCT found more disappointing results (4747. Lowe DA, Wu N, Rohdin-Bibby L, Moore AH, Kelly N, Liu YE, et al. Effects of Time-Restricted Eating on Weight Loss and Other Metabolic Parameters in Women and Men With Overweight and Obesity: The TREAT Randomized Clinical Trial [published online ahead of print, 2020 Sep 28]. JAMA Intern Med. 2020;180(11):1-9.). Lowe and cols. performed a randomized controlled trial in 116 overweight or individuals with obesity without imposing caloric restriction. One arm followed an 8-hour TRF (eating from 12:00-20:00) and the other received instructions for three structured meals a day. This exact feeding window was chosen to improve adherence, due to social and cultural reasons, allowing an early dinner. After 12 weeks, there was no difference in weight loss between the groups (-0.94 kg in the TRF versus -0.68 kg in the control arm), as well as no difference in general cardiometabolic parameters (glucose, insulin, lipids, and blood pressure). Fifty participants also performed a dual-energy-x-ray absorptiometry (DXA), and surprisingly, the TRF group had a higher decrease of appendicular lean mass compared to the control group. Indeed, 65% of the total weight loss in the TRF was lean mass, a result not expected, and a finding that deserves further analyses in future studies, which raises concerns on the applicability of this model in clinical practice. In the opposite direction, however, one study that evaluated 34 active men, performing resistance training randomized to a regular diet or TRF in a similar eight-hour window for eight weeks, showed fat mass (measured by DXA) decreased in TRF, without any decrease in muscle mass. An improvement of some inflammatory markers was also observed (4848. Moro T, Tinsley G, Bianco A, Marcolin G, Pacelli QF, Battaglia G, et al. Effects of eight weeks of time-restricted feeding (16/8) on basal metabolism, maximal strength, body composition, inflammation, and cardiovascular risk factors in resistance-trained males. J Transl Med. 2016;14(1):290.). Whether those differences on body composition observed relates to the different baseline characteristics of the studies participants (trained men versus individuals with overweight or obesity) remains to be determined.

Another recent study aimed to answer if a reduced feeding window could be more effective (4949. Cienfuegos S, Gabel K, Kalam F, Ezpeleta M, Wiseman E, Pavlou V, et al. Effects of 4- and 6-h Time-Restricted Feeding on Weight and Cardiometabolic Health: A Randomized Controlled Trial in Adults with Obesity [published online ahead of print, 2020 Jul 8]. Cell Metab. 2020;32(3):366-378.e3.). In this study, patients with obesity were randomized into three groups for eight weeks: 6-hour feeding window (1300 h to 1900 h), 4-hour feeding window (1500 h to 1900 h), and control (maintenance of usual diet). Given the circadian rhythm (discussed below), feeding during the night was not allowed in neither of the active arms. Surprisingly, regardless of the regimen (4 h or 6 h of feeding), individuals with restricted feeding windows lost a mean of 3.2% of the baseline weight. The weight loss achieved was similar to what was observed in the above mentioned pilot study, from the same group, with an 08h feeding protocol (4646. Gabel K, Hoddy KK, Haggerty N, Song J, Kroeger CM, Trepanowski JF, et al. Effects of 8-hour time restricted feeding on body weight and metabolic disease risk factors in obese adults: A pilot study. Nutr Healthy Aging. 2018;4(4):345-53.). The effect is almost certainly related to reduced consumption of calories, due to the reduced feeding schedule: their caloric intake was decreased by approximately 550 kcal/day, but it is possible that this reduction in intake was overestimated, as a 500 kcal restriction usually leads to higher weight loss in an eight-week -period. As an additional benefit, insulin sensitivity improved and oxidative stress markers decreased in both intervention groups. In the discussion, the authors believe this effect could be independent from the weight-loss, although no definite conclusion can be made, as this trial did not include an arm for continuous caloric restriction without fasting (4949. Cienfuegos S, Gabel K, Kalam F, Ezpeleta M, Wiseman E, Pavlou V, et al. Effects of 4- and 6-h Time-Restricted Feeding on Weight and Cardiometabolic Health: A Randomized Controlled Trial in Adults with Obesity [published online ahead of print, 2020 Jul 8]. Cell Metab. 2020;32(3):366-378.e3.).

Due to the low number of good-quality studies (that fortunately are increasing), we still have little evidence of a clear benefit of TRF compared to other protocols. The great advantage seems to restrict the consumption of calories during a period of the day, which, in the absence of super-compensation during the remaining hours, can reduce calories without the need to count them (44. Hoddy KK, Marlatt KL, Çetinkaya H, Ravussin E. Intermittent Fasting and Metabolic Health: From Religious Fast to Time-Restricted Feeding. Obesity (Silver Spring). 2020;28 Suppl 1(Suppl 1):S29-S37.,4646. Gabel K, Hoddy KK, Haggerty N, Song J, Kroeger CM, Trepanowski JF, et al. Effects of 8-hour time restricted feeding on body weight and metabolic disease risk factors in obese adults: A pilot study. Nutr Healthy Aging. 2018;4(4):345-53.). Nonetheless, the decrease in muscle mass observed in the study by Lowe and cols. is disturbing (4747. Lowe DA, Wu N, Rohdin-Bibby L, Moore AH, Kelly N, Liu YE, et al. Effects of Time-Restricted Eating on Weight Loss and Other Metabolic Parameters in Women and Men With Overweight and Obesity: The TREAT Randomized Clinical Trial [published online ahead of print, 2020 Sep 28]. JAMA Intern Med. 2020;180(11):1-9.). A question that arises is whether an equal feeding window performed early on in the day could have metabolic advantages and the role of physical activity in those results.

TIME-RESTRICTED FEEDING AND CIRCADIAN RHYTHM

Biological control of external time is vital for all living species (22. Mattson MP, Allison DB, Fontana L, Harvie M, Longo VD, Malaisse WJ, et al. Meal frequency and timing in health and disease. Proc Natl Acad Sci U S A. 2014;111(47):16647-53.,77. Asher G, Sassone-Corsi P. Time for food: the intimate interplay between nutrition, metabolism, and the circadian clock. Cell. 2015;161(1):84-92.). In mammals, the circadian control is regulated by the suprachiasmatic nucleus in the hypothalamus – our “biological clock” (5050. Stenvers DJ, Scheer FAJL, Schrauwen P, la Fleur SE, Kalsbeek A. Circadian clocks and insulin resistance. Nat Rev Endocrinol. 2019;15(2):75-89.). Circadian rhythms controlled by internal oscillators have an essential role in metabolic regulation (5050. Stenvers DJ, Scheer FAJL, Schrauwen P, la Fleur SE, Kalsbeek A. Circadian clocks and insulin resistance. Nat Rev Endocrinol. 2019;15(2):75-89.,5151. Challet E. The circadian regulation of food intake. Nat Rev Endocrinol. 2019;15(7):393-405.). In evolution, each species tends to feed during the active period of their day (day or night, depending on the species). Several animal studies suggest that feeding during the rest period leads to an abnormal metabolic profile related to the ectopic deposition of fat, due to, among other reasons, inferior decreased lipogenic capacity during this period (5252. Adamovich Y, Rousso-Noori L, Zwighaft Z, Neufeld-Cohen A, Golik M, Kraut-Cohen J, et al. Circadian clocks and feeding time regulate the oscillations and levels of hepatic triglycerides. Cell Metab. 2014;19(2):319-30.5454. Arble DM, Bass J, Laposky AD, Vitaterna MH, Turek FW. Circadian timing of food intake contributes to weight gain. Obesity (Silver Spring). 2009;17(11):2100-2.).

In humans, we know that individuals who have a later chronotype pattern have a worse metabolic profile and are exposed to an increased risk of weight gain, type 2 diabetes, and even cardiovascular outcomes. Still, many confounders prevent establishing a clear cause-effect (5555. Reutrakul S, Hood MM, Crowley SJ, Morgan MK, Teodori M, Knutson KL, et al. Chronotype is independently associated with glycemic control in type 2 diabetes. Diabetes Care. 2013;36(9):2523-9.5858. St-Onge MP, Ard J, Baskin ML, Chiuve SE, Johnson HM, Kris-Etherton P, et al. Meal Timing and Frequency: Implications for Cardiovascular Disease Prevention: A Scientific Statement From the American Heart Association. Circulation. 2017;135(9):e96-e121.). However, two RCTs performed one decade ago suggested that evening meals were associated with reduced fat mass, reduced HDL-cholesterol, increased LDL-cholesterol, increased blood pressure (in one of the trials), and increased fasting glucose (in the other one) (5959. Carlson O, Martin B, Stote KS, Golden E, Maudsley S, Najjar SS, et al. Impact of reduced meal frequency without caloric restriction on glucose regulation in healthy, normal-weight middle-aged men and women. Metabolism. 2007;56(12):1729-34.,6060. Stote KS, Baer DJ, Spears K, Paul DR, Harris GK, Rumpler WV, et al. A controlled trial of reduced meal frequency without caloric restriction in healthy, normal-weight, middle-aged adults. Am J Clin Nutr. 2007;85(4):981-8.). Recently, a study showed that after a weight-loss intervention protocol, late eaters had a lower weekly weight-loss rate compared to early eaters; however, the late eaters also had lower motivation and higher psychological barriers, suggesting that late eating could just be a marker of maladaptive eating, rather than it being biologically related to the poorer result (6161. Dashti HS, Gómez-Abellán P, Qian J, Esteban A, Morales E, Scheer FAJL, et al. Late eating is associated with cardiometabolic risk traits, obesogenic behaviors, and impaired weight loss [published online ahead of print, 2020 Oct 6]. Am J Clin Nutr. 2020;nqaa264.).

Another study to help elucidate the role of circadian rhythm consisted of a supervised 5-week cross-over pilot study in men with prediabetes aimed to evaluate if TRF with a 6-h feeding window and dinner not after 1500 h had metabolic advantages over an isocaloric feeding pattern, with a 12 h feeding window and 12-h fasting. In this controlled study, the TRF period increased insulin sensitivity, reduced blood pressure, reduced oxidative stress, and decreased appetite (66. Sutton EF, Beyl R, Early KS, Cefalu WT, Ravussin E, Peterson CM. Early Time-Restricted Feeding Improves Insulin Sensitivity, Blood Pressure, and Oxidative Stress Even without Weight Loss in Men with Prediabetes. Cell Metab. 2018;27(6):1212-21.e3.). As it was an isocaloric study, it did not aim to evaluate food intake, and no weight differences were observed; thus, differences between control and intervention phases cannot be attributed to weight loss. However, as there was no similar group with the nighttime feeding period, it is impossible to know whether the effects were related to the 18 hours of fasting or the absence of nocturnal food intake. Simultaneously, as a pilot- and proof-of-concept study, it did not assessed the feasibility, so we cannot infer if this pattern is sustainable in a larger population for a longer period.

A recent RCT evaluated if late-night dinner (2200 h) could have a different metabolic impact than earlier dinner (1800 h) (6262. Gu C, Brereton N, Schweitzer A, Cotter M, Duan D, Børsheim E, et al. Metabolic Effects of Late Dinner in Healthy Volunteers-A Randomized Crossover Clinical Trial. J Clin Endocrinol Metab. 2020;105(8):2789-802.). Twenty healthy volunteers received the same meals on different days in a lab setting. Late dinner was associated with higher glucose, triglycerides peak delay, and reduced fatty acids oxidation, which could contribute to metabolic disturbances in the long term. Interestingly, however, the effects were more pronounced on habitual early sleepers, suggesting that individual social and biological differences in circadian rhythms can influence results. These differences have already been shown, regarding skipping breakfast, in which habitual “breakfast skippers” have very different responses than “breakfast eaters” (6363. Thomas EA, Higgins J, Bessesen DH, McNair B, Cornier MA. Usual breakfast eating habits affect response to breakfast skipping in overweight women. Obesity (Silver Spring). 2015;23(4):750-9.,6464. LeCheminant GM, LeCheminant JD, Tucker LA, Bailey BW. A randomized controlled trial to study the effects of breakfast on energy intake, physical activity, and body fat in women who are nonhabitual breakfast eaters. Appetite. 2017;112:44-51.).

Further, elucidation is needed for establishing causation for time-restricted feeding. Does regular breakfast skipping (or frequent nighttime eating) lead to metabolic adaptations? There is a possibility that the preference for eating or not eating breakfast or the time of having dinner is, at least partially, biologically determined, and a marker, instead of a cause, of a metabolic disorder.

ADDITIONAL BENEFITS FROM INTERMITTENT FASTING

Many of the cited mechanisms of IF on animal models are related to the improvement of chronic conditions much beyond obesity itself.

Regarding type 2 diabetes (T2D), many of the proposed benefits of IF are similar to what has been previously discussed: weight loss and improved insulin sensitivity (11. de Cabo R, Mattson MP. Effects of Intermittent Fasting on Health, Aging, and Disease. [published correction appears in N Engl J Med. 2020 Jan 16;382(3):298] [published correction appears in N Engl J Med. 2020 Mar 5;382(10):978]. N Engl J Med. 2019;381(26):2541-51.,3030. Welton S, Minty R, O’Driscoll T, Willms H, Poirier D, Madden S, et al. Intermittent fasting and weight loss: Systematic review. Can Fam Physician. 2020;66(2):117-25.,6565. Arnason TG, Bowen MW, Mansell KD. Effects of intermittent fasting on health markers in those with type 2 diabetes: A pilot study. World J Diabetes. 2017;8(4):154-64.). A reduced number of meals can also be useful to avoid several glycemic excursions during the day. Some studies have shown that the reduction of the total number of meals can be a helpful strategy (6565. Arnason TG, Bowen MW, Mansell KD. Effects of intermittent fasting on health markers in those with type 2 diabetes: A pilot study. World J Diabetes. 2017;8(4):154-64.6767. Jakubowicz D, Landau Z, Tsameret S, Wainstein J, Raz I, Ahren B, et al. Reduction in Glycated Hemoglobin and Daily Insulin Dose Alongside Circadian Clock Upregulation in Patients With Type 2 Diabetes Consuming a Three-Meal Diet: A Randomized Clinical Trial. Diabetes Care. 2019;42(12):2171-80.). In one study in women with T2D, eating two meals a day (in a maximum of a ten-hour interval) was superior to eating 6 smaller meals daily in weight loss and glycemic control (6666. Kahleova H, Belinova L, Malinska H, Oliyarnyk O, Trnovska J, Skop V, et al. Eating two larger meals a day (breakfast and lunch) is more effective than six smaller meals in a reduced-energy regimen for patients with type 2 diabetes: a randomised crossover study [published correction appears in Diabetologia. 2015 Jan;58(1):205]. Diabetologia. 2014;57(8):1552-60.). This is an important message, beyond IF itself. Historically, patients with T2D were advised to eat small amounts of food several times a day to avoid hypoglycemia. This recommendation, based on current knowledge, can be counterproductive (6868. Kahleova H, Belinova L, Hill M, Pelikanova T. Do patients with type 2 diabetes still need to eat snacks? Eur J Clin Nutr. 2015;69(6):755-6.). Clearly, in patients using exogenous insulin or sulfonylureas, dose adjustment will be necessary if IF is implemented, but overall, the risk of hypoglycemia is low (6969. Grajower MM, Horne BD. Clinical Management of Intermittent Fasting in Patients with Diabetes Mellitus. Nutrients. 2019;11(4):873.).

The longer study performed evaluating IF for T2D to date (52 weeks), did not observe superiority of IF, regarding HbA1c or weight loss (3636. Carter S, Clifton PM, Keogh JB. Effect of Intermittent Compared With Continuous Energy Restricted Diet on Glycemic Control in Patients With Type 2 Diabetes: A Randomized Noninferiority Trial. JAMA Netw Open. 2018;1(3):e180756.). In this context, IF regimens can be considered and individualized in patients with T2D, but similar to what was already discussed in obesity, it should be clear that it is an alternative to daily caloric restriction, rather than a superior intervention.

de Cabo and Mattson provided a very compelling and complete discussion of additional promising benefits of IF in cancer, aging, neuroprotection, and more (11. de Cabo R, Mattson MP. Effects of Intermittent Fasting on Health, Aging, and Disease. [published correction appears in N Engl J Med. 2020 Jan 16;382(3):298] [published correction appears in N Engl J Med. 2020 Mar 5;382(10):978]. N Engl J Med. 2019;381(26):2541-51.). However, it is important to note that most of the available data discussed by de Cabo and Mattson come from caloric restriction experiments in animal models (11. de Cabo R, Mattson MP. Effects of Intermittent Fasting on Health, Aging, and Disease. [published correction appears in N Engl J Med. 2020 Jan 16;382(3):298] [published correction appears in N Engl J Med. 2020 Mar 5;382(10):978]. N Engl J Med. 2019;381(26):2541-51.). Whilst in those models, caloric restriction is achieved through a TRF (as animals tend to eat in their active phase), it is not possible to conclude whether benefits are from fasting, caloric restriction, or both. Human studies are just emerging.

In the ADF study by Stekovic and cols., in a healthy, non-obese, middle-aged population, the age-associated inflammatory marker sICAM-1 was lower in the intervention arm (3939. Stekovic S, Hofer SJ, Tripolt N, Aon MA, Royer P, Pein L, et al. Alternate Day Fasting Improves Physiological and Molecular Markers of Aging in Healthy, Non-obese Humans [published correction appears in Cell Metab. 2020 Apr 7;31(4):878-881]. Cell Metab. 2019;30(3):462-76.e6.). Aging is a complex biological process, and every attempt to prove that an intervention can slow it should be taken cautiously (7070. Redman LM, Smith SR, Burton JH, Martin CK, Il’yasova D, Ravussin E. Metabolic Slowing and Reduced Oxidative Damage with Sustained Caloric Restriction Support the Rate of Living and Oxidative Damage Theories of Aging. Cell Metab. 2018;27(4):805-15.e4.). RCTs designed to show anti-aging properties are tough to create, given the necessary long-term. Thus, metabolic and oxidative parameters are always used as surrogate markers, and as such, they are imperfect (7171. Flanagan EW, Most J, Mey JT, Redman LM. Calorie Restriction and Aging in Humans. Annu Rev Nutr. 2020;40:105-33.). Even with all these difficulties, we expect several studies to come about in the following years.

It is also important to reemphasize that we cannot directly extrapolate data from animal studies. If in rat models, high levels of ketone bodies are achieved after 16h fasting, in humans, it can take much longer, up to 48 hours, as already mentioned (1111. Mattson MP, Longo VD, Harvie M. Impact of intermittent fasting on health and disease processes. Ageing Res Rev. 2017;39:46-58.,4444. Cahill GF Jr. Starvation in man. N Engl J Med. 1970;282(12):668-75.,4545. Longo VD, Mattson MP. Fasting: molecular mechanisms and clinical applications. Cell Metab. 2014;19(2):181-92.). In this context, since long-term fasting is harder to be performed, a group of researchers from California proposed a “fasting-mimicking diet” (FMD), which is patented and commercialized in the USA (7272. Brandhorst S, Choi IY, Wei M, Cheng CW, Sedrakyan S, Navarrete G, et al. A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan. Cell Metab. 2015;22(1):86-99.,7373. Wei M, Brandhorst S, Shelehchi M, Mirzaei H, Cheng CW, Budniak J, et al. Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease. Sci Transl Med. 2017;9(377):eaai8700.). FMD consists of plant-based, whole food diets, rich in essential fatty acids, vitamins, and minerals consumed for five consecutive days, which does not activate IGF1 and insulin pathways (7474. Brandhorst S, Longo VD. Protein Quantity and Source, Fasting-Mimicking Diets, and Longevity. Adv Nutr. 2019;10(Suppl_4):S340-50.). As such, it would theoretically reproduce the scenario of fasting in the organism (7272. Brandhorst S, Choi IY, Wei M, Cheng CW, Sedrakyan S, Navarrete G, et al. A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan. Cell Metab. 2015;22(1):86-99.). The proposed benefits are reduced inflammation and aging, with a potential effect in several chronic non-communicable diseases. Although some studies showed improvement of inflammatory and oxidative stress markers, there is no evidence regarding significant clinical outcomes (7373. Wei M, Brandhorst S, Shelehchi M, Mirzaei H, Cheng CW, Budniak J, et al. Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease. Sci Transl Med. 2017;9(377):eaai8700.,7474. Brandhorst S, Longo VD. Protein Quantity and Source, Fasting-Mimicking Diets, and Longevity. Adv Nutr. 2019;10(Suppl_4):S340-50.).

In conclusion, intermittent fasting has gained much attention as a popular weight-loss strategy over the last few years. Controlled studies demonstrated that IF (which can have very different protocols) is a safe alternative to daily caloric restriction, with similar weight loss results. Nonetheless, its effects on weight are directly related to caloric restriction and not the metabolic effects of fasting. More work is needed to establish if prolonged fasting can have a weight-independent impact on insulin sensitivity and other metabolic and oxidative markers in humans, as shown in animals. A comprehensive summary of the main unanswered questions can be found in Table 2.

Table 2
Unanswered questions and rationale for them

Results from trials are heterogeneous, and due to that, a personalized approach is necessary. The search for clinical markers able to predict responses is appealing. As most trials are small, many discussed results should be interpreted cautiously. Lack of statistical power to show differences in weight loss and substitutive markers is one crucial factor that should be considered when evaluating IF RCTs.

While there is no definitive conclusion, IF clearly has some advantages and disadvantages. A summary of the popular claims pro and con to IF, as well as the current state of the evidence can be found in Table 3. Against IF, long-term trials suggest lower adherence in the long-term compared to daily caloric restriction (or an increase in caloric intake on fasting days and a decrease in feeding days that resembles a routine caloric restriction protocol). Favoring MADF and ADF is that it can be easier to follow, since it generally is not necessary to count calories, or at least permits regular eating on the majority of the days. Regarding TRF, the imposed restriction on timing, rather than foods, can also be easier to follow for some. Different IF protocols can have direct effects on insulin sensitivity in insulin-resistant individuals (although data are still equivocal), and restricting food at night could also have a positive impact on the metabolic profile. Nevertheless, “inversed” TRF, with food restriction in the morning, is less studied and theoretically goes against our circadian biology.

Table 3
Popular claims (pro and agains) to IF regimens

Benefits on aging, inflammation, and neuroprotection in humans are still scarce. Fasting mimicking-diets are being studied with interesting results, and we can expect further elucidative research in the area.

  • Funding: none.

Acknowledgments:

none.

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Publication Dates

  • Publication in this collection
    18 Jan 2021
  • Date of issue
    Feb 2021

History

  • Received
    18 Aug 2020
  • Accepted
    10 Nov 2020
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