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longevity/​fasting directory


“Life-long Dietary Restrictions Have Negligible or Damaging Effects on Late-life Cognitive Performance: A Key Role for Genetics in Outcomes”, Ouellette et al 2022

“Life-long Dietary Restrictions have Negligible or Damaging Effects on Late-life Cognitive Performance: A Key Role for Genetics in Outcomes”⁠, Andrew R. Ouellette, Niran Hadad, Andrew Deighan, Laura Robinson, Kristen O’Connell, Adam Freund, Gary A. Churchill et al (2022-04-26):

Several studies report that caloric restriction (CR) or intermittent fasting (IF) can improve cognition, while others report limited or no cognitive benefits. Here, we compare the effects of 20% CR, 40% CR, 1-day IF, and 2-day IF feeding paradigms to ad libitum controls (AL) on Y-maze working memory and contextual fear memory (CFM) in a large population of Diversity Outbred mice that model the genetic diversity of humans. While CR and IF interventions improve lifespan, we observed no enhancement of working memory or CFM in mice on these feeding paradigms, and report 40% CR to be damaging in the context of long-term memory. Using Quantitative Trait Loci mapping, we identified the gene Slc16a7 to be associated with late-life long-term memory outcomes in mice on lifespan promoting feeding paradigms. Limited utility of dieting and fasting on memory in mice that recapitulate genetic diversity in the human population highlights the need for anti-aging therapeutics that promote cognitive function, with a neuronal monocarboxylate transporter encoded by Slc16a7 highlighted as novel target.

“Deep Phenotyping and Lifetime Trajectories Reveal Limited Effects of Longevity Regulators on the Aging Process in C57BL/6J Mice”, Xie et al 2022

“Deep Phenotyping and Lifetime Trajectories Reveal Limited Effects of Longevity Regulators on the Aging Process in C57BL/6J Mice”⁠, Kan Xie, Helmut Fuchs, Enzo Scifo, Dan Liu, Ahmad Aziz, Juan Antonio Aguilar-Pimentel, Oana Veronica Amarie et al (2022-03-27; similar):

Current concepts regarding the biology of aging are based on studies aimed at identifying factors regulating natural lifespan. However, lifespan as a sole proxy measure for aging can be of limited value because it may be restricted by specific sets of pathologies, rather than by general physiological decline. Here, we employed large-scale phenotyping to analyze hundreds of phenotypes and thousands of molecular markers across tissues and organ systems in a single study of aging male C57BL/​6J mice. For each phenotype, we established lifetime profiles to determine when age-dependent phenotypic change is first detectable relative to the young adult baseline. We examined central genetic and environmental lifespan regulators (putative anti-aging interventions, PAAIs; the following PAAIs were examined: mTOR loss-of-function, loss-of-function in growth hormone signaling, dietary restriction) for a possible countering of the signs and symptoms of aging. Importantly, in our study design, we included young treated groups of animals, subjected to PAAIs prior to the onset of detectable age-dependent phenotypic change. In parallel to our studies in mice, we assessed genetic variants for their effects on age-sensitive phenotypes in humans. We observed that, surprisingly, many PAAI effects influenced phenotypes long before the onset of detectable age-dependent changes, rather than altering the rate at which these phenotypes developed with age. Accordingly, this subset of PAAI effects does not reflect a targeting of age-dependent phenotypic change. Overall, our findings suggest that comprehensive phenotyping, including the controls built in our study, is critical for the investigation of PAAIs as it facilitates the proper interpretation of the mechanistic mode by which PAAIs influence biological aging.

“Antiaging Diets: Separating Fact from Fiction”, Lee et al 2021

2021-lee.pdf: “Antiaging diets: Separating fact from fiction”⁠, Mitchell B. Lee, Cristal M. Hill, Alessandro Bitto, Matt Kaeberlein (2021-11-19; similar):

Caloric restriction has been known for nearly a century to extend life span and delay age-associated pathology in laboratory animals. More recently, alternative “antiaging” diet modalities have been described that provide new mechanistic insights and potential clinical applications. These include intermittent fasting⁠, fasting-mimicking diets, ketogenic diets, time-restricted feeding, protein restriction⁠, and dietary restriction of specific amino acids.

Despite mainstream popularization of some of these diets, many questions remain about their efficacy outside of a laboratory setting.

Studies of these interventions support at least partially overlapping mechanisms of action and provide insights into what appear to be highly conserved mechanisms of biological aging.

Caution around the fountain of youth: The scientific and popular literature is full of claims for diets that delay or reverse the aging process (at least in model organisms). But how do these interventions work? Is it the amount of food, the timing of food intake, the proportion of certain macronutrients? In a Review, Lee et al 2021 explore the fact and fiction of dietary prescriptions for a healthier and longer life. They propose that one unifying concept may be convergence on the signaling pathway mediated by the protein kinase mTOR (“mechanistic target of rapamycin”). Another conclusion is that the efficacy and safety of these diets for humans largely remain to be established.

Background: Reduced caloric intake without malnutrition is the oldest known life span-extending intervention. Laboratory studies throughout the 20th century established and confirmed the benefits of caloric restriction (CR) in multiple model systems. CR not only increased life span across evolutionarily distant organisms but also reduced age-associated disease burden and functional decline in these studies. Epidemiological data from human populations is also generally consistent with the idea that lower caloric intake is associated with increased life expectancy. In recent years, numerous diet modalities that are purported to be “antiaging” have sprung from these observations. These diets restrict particular macronutrients (carbohydrates or protein) or feeding intervals and can be divided into those that impose reduced caloric intake versus those that are isocaloric to control diets.

Advances: We evaluated several of the most popular antiaging diets, including CR, intermittent fasting, fasting-mimicking diets, ketogenic diets, time-restricted feeding, protein restriction, and essential amino acid restriction. By characterizing these nutritional interventions in comparison with classical CR, we gained numerous insights. Many studies fail to control for reduced caloric intake in the diet group, making their effects impossible to decouple from CR. Although often presented as uniformly beneficial, the effects of CR on life span are highly dependent on genotype and, in some cases, cause reduced survival. Despite their limitations, these studies have greatly improved our understanding of the cellular response to low nutrient availability. A picture is beginning to emerge of a complex network composed of multiple signaling pathways that converge on key molecular hubs; foremost among these is the mechanistic target of rapamycin (mTOR). Because mTOR and other components of this network are well-studied drug targets, there continues to be considerable interest in pharmacologically targeting this network to increase longevity and health span. Human studies, both correlative and controlled, are consistent with health benefits conferred by a CR diet. However, it remains unresolved whether these benefits are a consequence of modulating the aging process itself or are simply the result of avoiding obesity. Several unresolved questions suggest caution when considering whether to recommend or implement any of these diets among the healthy general public. Among these is understanding how genetic and environmental variation modify diet response, especially in understudied populations and in the context of environmental challenges such as, for example, a global viral pandemic.

Outlook: CR and other antiaging diets have yielded important insights into the complex and evolutionarily conserved signaling pathways that transduce information regarding environmental nutrient availability into a physiological response to promote healthy longevity. This understanding, in turn, has opened the door to a new generation of longevity-promoting interventions that mimic molecular responses to nutrient deprivation. Although CR and other diets hold promise, additional data from carefully controlled studies is needed before broadly recommending or implementing these diets, or other interventions, for otherwise healthy people. Human genetic and environmental variation combined with the challenge of modeling human aging in ultimately dissimilar mammalian model systems pose fundamental limitations to our current ability to predictably translate these findings to people. From a pragmatic perspective, even if these challenges can be overcome, widespread adoption of dietary interventions for healthy longevity seem unrealistic. We therefore suggest that alternative, nondietary strategies with the potential for public uptake should therefore be pursued. In particular, validated biomarkers of biological aging are required to match intervention to each person’s distinct genetic and environmental context and thereby optimize individual healthy life span. Future research directed at clarifying the underlying mechanisms involved in eliciting the longevity-promoting response to CR, and how this differs among individuals, should one day help us realize a true precision geroscience approach.

“Once-daily Feeding Is Associated With Better Cognitive Function and Health in Companion Dogs: Results from the Dog Aging Project”, Bray et al 2021

“Once-daily feeding is associated with better cognitive function and health in companion dogs: Results from the Dog Aging Project”⁠, Emily E. Bray, Zihan Zheng, M. Katherine Tolbert, Brianah M. McCoy, Dog Aging Project Consortium, Matt Kaeberlein et al (2021-11-11; ; similar):

A variety of diets have been studied for possible anti-aging effects. In particular, studies of isocaloric time-restricted feeding in laboratory rodents have found evidence of beneficial health outcomes. Companion dogs represent an unique opportunity to study diet in a large mammal that shares human environments. The Dog Aging Project has been collecting data on thousands of companion dogs of all different ages, sizes, and breeds since 2019. We leveraged this diverse cross-sectional dataset to investigate associations between feeding frequency and cognitive function (n = 10,474) as well as nine broad categories of health outcomes (n = 24,238). Controlling for sex, age, breed, and other potential confounders, we found that dogs fed once daily rather than more frequently had lower mean scores on a cognitive dysfunction scale, and lower odds of having gastrointestinal, dental, orthopedic, kidney/​urinary, and liver/​pancreas disorders. Therefore, our findings suggest that once-a-day feeding in dogs is associated with improved health across multiple body systems.

“Daily Caloric Restriction Limits Tumor Growth More Effectively Than Caloric Cycling regardless of Dietary Composition”, Pomatto-Watson et al 2021

“Daily caloric restriction limits tumor growth more effectively than caloric cycling regardless of dietary composition”⁠, Laura C. D. Pomatto-Watson, Monica Bodogai, Oye Bosompra, Jonathan Kato, Sarah Wong, Melissa Carpenter et al (2021-10-27; similar):

Cancer incidence increases with age and is a leading cause of death. Caloric restriction (CR) confers benefits on health and survival and delays cancer.

However, due to CR’s stringency, dietary alternatives offering the same cancer protection have become increasingly attractive. Short cycles of a plant-based diet designed to mimic fasting (FMD) are protective against tumorigenesis without the chronic restriction of calories. Yet, it is unclear whether the fasting time, level of dietary restriction, or nutrient composition is the primary driver behind cancer protection.

Using a breast cancer model in mice, we compare the potency of daily CR to that of periodic caloric cycling on FMD or an isocaloric standard laboratory chow against primary tumor growth and metastatic burden.

Here, we report that daily CR provides greater protection against tumor growth and metastasis to the lung, which may be in part due to the unique immune signature observed with daily CR.

“Fasting-mimicking Diet Is Safe and Reshapes Metabolism and Antitumor Immunity in Cancer Patients”, Vernieri et al 2021

“Fasting-mimicking diet is safe and reshapes metabolism and antitumor immunity in cancer patients”⁠, Claudio Vernieri, Giovanni Fuca, Francesca Ligorio, Veronica Huber, Andrea Vingiani, Fabio Iannelli, Alessandra Raimondi et al (2021-10-22; similar):

In tumor-bearing mice, cyclic fasting or fasting-mimicking diets (FMDs) enhance the activity of antineoplastic treatments by modulating systemic metabolism and boosting antitumor immunity.

Here we conducted a clinical trial to investigate the safety and biological effects of cyclic, 5-day FMD in combination with standard antitumor therapies.

In 101 patients, the FMD was safe, feasible, and resulted in a consistent decrease of blood glucose and growth factor concentration, thus recapitulating metabolic changes that mediate fasting/​FMD anticancer effects in preclinical experiments. Integrated transcriptomic and deep-phenotyping analyses revealed that FMD profoundly reshapes anticancer immunity by inducing the contraction of peripheral blood immunosuppressive myeloid and regulatory T-cell compartments, paralleled by enhanced intratumor T-helper 1/​cytotoxic responses and an enrichment of interferon-gamma and other immune signatures associated with better clinical outcomes in cancer patients.

Our findings lay the foundations for phase II/​III clinical trials aimed at investigating FMD antitumor efficacy in combination with standard antineoplastic treatments.

“Rilmenidine Mimics Caloric Restriction via the Nischarin I1-imidazoline Receptor to Extend Lifespan in C. Elegans”, Bennett et al 2021

“Rilmenidine mimics caloric restriction via the nischarin I1-imidazoline receptor to extend lifespan in C. elegans”⁠, Dominic F. Bennett, Anita Goyala, Cyril Statzer, Charles W. Beckett, Alexander Tyshkovskiy, Vadim N. Gladyshev et al (2021-10-15; similar):

Caloric restriction increases lifespan across species and has health benefits in humans. Because complying with a low-calorie diet is challenging, here we investigated pharmacological interventions mimicking the benefits of caloric restriction. Searching for compounds that elicit a similar gene expression signature to caloric restriction, we identified rilmenidine, an I1-imidazoline receptor agonist and prescription medication for the treatment of hypertension. We then show that treating C. elegans with rilmenidine at young and older ages increases lifespan. We also demonstrate that the stress-resilience, healthspan, and lifespan benefits upon rilmenidine treatment in worms are mediated by the I1-imidazoline receptor nish-1, implicating this receptor as a potential longevity target. Furthermore, we show that rilmenidine treatment increased ERK phosphorylation via NISH-1. Consistent with the shared caloric-restriction-mimicking gene signature, supplementing rilmenidine to caloric restricted C. elegans, genetic reduction of TORC1 function, or rapamycin treatment did not further increase lifespan. The rilmenidine-induced longevity required the transcription factors FOXO/​DAF-16 and NRF1,2,3/​SKN-1, both important for caloric restriction-mediated longevity. Furthermore, we find that autophagy, but not AMPK signaling, was needed for rilmenidine-induced longevity. Lastly, we find that treating mice with rilmenidine showed transcriptional changes in liver and kidney similar to caloric restriction. Overall, our findings reveal rilmenidine as a caloric restriction mimetic and as a novel geroprotective compound.

“Intermittent and Periodic Fasting, Hormones, and Cancer Prevention”, Salvadori et al 2021

“Intermittent and Periodic Fasting, Hormones, and Cancer Prevention”⁠, Giulia Salvadori, Mario Giuseppe Mirisola, Valter D. Longo (2021-09-13; similar):

Hormonal and growth factor alterations, related to an elevated food consumption and excessive adiposity, affect the regulation of genes involved in cellular processes including proliferation, differentiation and DNA repair, allowing cells to survive and proliferate despite the accumulation of mutations which lead to malignant transformation. The growth hormone/​insulin growth factor-1 (GH/​IGF-1) / insulin pathway and its downstream effectors, in fact, are known to promote aging and/​or age-related diseases, including cancer, in many model organisms. The restriction of nutrients is established to have strong effects on levels of hormones and growth factors, delaying the incidence of age-related diseases and prolonging lifespan. Here, we summarize the effects caused by different nutrition intervention strategies on cellular damage, aging and cancer.

The restriction of proteins, amino acids or sugars can have profound effects on the levels of hormones and factors including growth hormone, IGF-1 and insulin. In turn, these can regulate intracellular signaling pathways as well as cellular damage and aging, but also multisystem regeneration. Both intermittent (IF) and periodic fasting (PF) have been shown to have both acute and long-term effects on these hormones. Here, we review the effects of nutrients and fasting on hormones and genes established to affect aging and cancer. We describe the link between dietary interventions and genetic pathways affecting the levels of these hormones and focus on the mechanisms responsible for the cancer preventive effects. We propose that IF and PF can reduce tumor incidence both by delaying aging and preventing DNA damage and immunosenescence and also by killing damaged, pre-cancerous and cancer cells.

[Keywords: fasting, growth hormones, aging, DNA damage, cancer prevention]

“Intermittent Fasting Enhances Long-term Memory Consolidation, Adult Hippocampal Neurogenesis, and Expression of Longevity Gene Klotho”, Dias et al 2021

“Intermittent fasting enhances long-term memory consolidation, adult hippocampal neurogenesis, and expression of longevity gene Klotho”⁠, Gisele Pereira Dias, Tytus Murphy, Doris Stangl, Selda Ahmet, Benjamin Morisse, Alina Nix, Lindsey J. Aimone et al (2021-05-25; similar):

Daily calorie restriction (CR) and intermittent fasting (IF) enhance longevity and cognition but the effects and mechanisms that differentiate these 2 paradigms are unknown.

We examined whether IF in the form of every-other-day feeding enhances cognition and adult hippocampal neurogenesis (AHN) when compared to a matched 10% daily CR intake and ad libitum conditions.

After 3 months under IF, female C57BL6 mice exhibited improved long-term memory retention. IF increased the number of BrdU-labeled cells and neuroblasts in the hippocampus, and microarray analysis revealed that the longevity gene Klotho (Kl) was upregulated in the hippocampus by IF only. Furthermore, we found that downregulating Kl in human hippocampal progenitor cells led to decreased neurogenesis, whereas Kl overexpression increased neurogenesis. Finally, histological analysis of Kl knockout mice brains revealed that Kl is required for AHN, particularly in the dorsal hippocampus.

These data suggest that IF is superior to 10% CR in enhancing memory and identifies Kl as a novel candidate molecule that regulates the effects of IF on cognition likely via AHN enhancement.

“Microbiome Connections With Host Metabolism and Habitual Diet from 1,098 Deeply Phenotyped Individuals”, Asnicar et al 2021

2021-asnicar.pdf: “Microbiome connections with host metabolism and habitual diet from 1,098 deeply phenotyped individuals”⁠, Francesco Asnicar, Sarah E. Berry, Ana M. Valdes, Long H. Nguyen, Gianmarco Piccinno, David A. Drew, Emily Leeming et al (2021-01-11; ⁠, ; similar):

The gut microbiome is shaped by diet and influences host metabolism; however, these links are complex and can be unique to each individual.

We performed deep metagenomic sequencing of 1,203 gut microbiomes from 1,098 individuals enrolled in the Personalised Responses to Dietary Composition Trial (PREDICT 1) study, whose detailed long-term diet information, as well as hundreds of fasting and same-meal postprandial cardiometabolic blood marker measurements were available.

We found many statistically-significant associations between microbes and specific nutrients, foods, food groups and general dietary indices, which were driven especially by the presence and diversity of healthy and plant-based foods. Microbial biomarkers of obesity were reproducible across external publicly available cohorts and in agreement with circulating blood metabolites that are indicators of cardiovascular disease risk. While some microbes, such as Prevotella copri and Blastocystis spp., were indicators of favorable postprandial glucose metabolism, overall microbiome composition was predictive for a large panel of cardiometabolic blood markers including fasting and postprandial glycemic, lipemic and inflammatory indices.

The panel of intestinal species associated with healthy dietary habits overlapped with those associated with favorable cardiometabolic and postprandial markers, indicating that our large-scale resource can potentially stratify the gut microbiome into generalizable health levels in individuals without clinically manifest disease.

“The Potential of Resveratrol to Act As a Caloric Restriction Mimetic Appears to Be Limited: Insights from Studies in Mice”, Pallauf et al 2020

2020-pallauf.pdf: “The Potential of Resveratrol to Act as a Caloric Restriction Mimetic Appears to Be Limited: Insights from Studies in Mice”⁠, Kathrin Pallauf, Ilka Günther, Gianna Kühn, Dawn Chin, Sonia de Pascual-Teresa, Gerald Rimbach (2020-12-03; similar):

Caloric restriction (CR) has been shown repeatedly to prolong the lifespan in laboratory animals, with its benefits dependent on molecular targets forming part of the nutrient signaling network, including the NAD-dependent deacetylase silent mating type information regulation 2 homologue 1 (SIRT1). It has been hypothesized that the stilbene resveratrol (RSV) may counteract age-related and obesity-related diseases similarly to CR. In yeast and worms, RSV-promoted longevity also depended on SIRT1. While it remains unclear whether RSV can prolong lifespans in mammals, some studies in rodents supplemented with RSV have reported lowered body weight (BW) and fat mass, improved insulin sensitivity, lowered cholesterol levels, increased fitness, and mitochondrial biogenesis. Molecular mechanisms possibly leading to such changes include altered gene transcription and activation of SIRT1, AMP-activated kinase (AMPK), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A). However, some mouse models did not benefit from RSV treatment to the same extent as others. We conducted a literature search on PubMed (15 April, 2020) for trials directly comparing RSV application to CR feeding in mice. In most studies retrieved by this systematic PubMed search, mice supplemented with RSV did not show statistically-significant reductions of BW, glucose, or insulin. Moreover, in some of these studies, RSV and CR treatments affected molecular targets differently and/​or findings on RSV and CR impacts varied between trials. We discuss those RSV-induced changes in gene transcription hypothesized to partly counteract age-related alterations. Although there may be a moderate effect of RSV supplementation on parameters such as insulin sensitivity toward a more CR-like profile in mice, data are inconsistent. Likewise, RSV supplementation trials in humans report controversial findings. While we consider that RSV may, under certain circumstances, moderately mimic some aspects of CR, current evidence does not fully support its use to prevent or treat age-related or obesity-related diseases.

“Effects of Caloric Restriction on Human Physiological, Psychological, and Behavioral Outcomes: Highlights from CALERIE Phase 2”, Dorling et al 2020

2020-dorling.pdf: “Effects of caloric restriction on human physiological, psychological, and behavioral outcomes: highlights from CALERIE phase 2”⁠, James L. Dorling, Stephan van Vliet, Kim M. Huffman, William E. Kraus, Manjushri Bhapkar, Carl F. Pieper et al (2020-09-17; similar):

Caloric restriction (CR) is a strategy that attenuates aging in multiple nonhuman species. The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trials are part of a research program aiming to test the effects of CR on aging and longevity biomarkers in humans.

Building on CALERIE phase 1, CALERIE phase 2 (CALERIE 2) was the largest study to date to assess sustained CR in healthy humans without obesity. In a 24-month randomized controlled trial comprising 218 participants at baseline, CALERIE 2 showed that moderate CR, 11.9% on average, induced improvements in aging-related biomarkers without adversely affecting psychological or behavioral outcomes.

The objectives of this report are to summarize and review the highlights of CALERIE 2 and report previously unpublished results on eating disorder symptoms and cognitive function. This article specifically summarizes the physiological, psychological, aging, behavioral, and safety results of the trial. Also provided are research directions beyond CALERIE 2 that highlight important opportunities to investigate the role of CR in aging, longevity, and health span in humans.

“The Daytime Feeding Frequency Affects Appetite-regulating Hormones, Amino Acids, Physical Activity, and Respiratory Quotient, but Not Energy Expenditure, in Adult Cats Fed Regimens for 21 Days”, Camara et al 2020

“The daytime feeding frequency affects appetite-regulating hormones, amino acids, physical activity, and respiratory quotient, but not energy expenditure, in adult cats fed regimens for 21 days”⁠, Alexandra Camara, Adronie Verbrugghe, Cara Cargo-Froom, Kylie Hogan, Trevor J. DeVries, Andrea Sanchez et al (2020-08-18; ; backlinks; similar):

The effects of feeding frequency on postprandial response of circulating appetite-regulating hormones, insulin, glucose and amino acids, and on physical activity, energy expenditure, and respiratory quotient were studied in healthy adult cats⁠. Two experiments were designed as a 2×3 replicated incomplete Latin square design. Eight cats, with an average body weight (BW) of 4.34 kg ± 0.04 and body condition score (BCS) of 5.4 ± 1.4 (9 point scale), were fed isocaloric amounts of a commercial adult maintenance canned cat food either once (0800 h) or four times daily (0800 h, 1130 h, 1500 h, 1830 h). Study 1 consisted of three 21-d periods. On day 14, two fasted and 11 postprandial blood samples were collected over 24 hours to measure plasma concentrations of ghrelin, GLP-1, GIP, leptin, PYY, insulin and amino acids, and whole blood glucose. Physical activity was monitored from day 15 to 21 of each period. In Study 2 indirect calorimetry was performed on the last day of each period. Body weight was measured weekly and feed intake recorded daily in both experiments. No effect of feeding regimen on BW was detected. Cats eating four times daily had lesser plasma concentrations of GIP and GLP-1 (p < 0.05) and tended to have lesser plasma PYY concentrations (p < 0.1). Plasma leptin and whole blood glucose concentrations did not differ between regimens (p > 0.1). Cats fed once daily had a greater postprandial plasma amino acid response, and greater plasma ghrelin and insulin concentrations (p < 0.05). Physical activity was greater in cats fed four times (p < 0.05), though energy expenditure was similar between treatments at fasting and in postprandial phases. Finally, cats eating one meal had a lower fasting respiratory quotient (p < 0.05). Overall, these data indicate that feeding once a day may be a beneficial feeding management strategy for indoor cats to promote satiation and lean body mass.

“Is Caloric Restriction Associated With Better Healthy Aging Outcomes? A Systematic Review and Meta-Analysis of Randomized Controlled Trials”, Caristia et al 2020

“Is Caloric Restriction Associated with Better Healthy Aging Outcomes? A Systematic Review and Meta-Analysis of Randomized Controlled Trials”⁠, Silvia Caristia, Marta De Vito, Andrea Sarro, Alessio Leone, Alessandro Pecere, Angelica Zibetti, Nicoletta Filigheddu et al (2020; similar):

Background: Global dietary patterns have gradually shifted toward a ‘western type’ with progressive increases in rates of metabolic imbalance. Recently, animal and human studies have revealed positive effects of caloric restriction (CR) on many health domains, giving new knowledge for prevention of ill and health promotion; Methods: We conducted a systematic review (SR) of randomized controlled trials (RCTs) investigating the role of CR on health status in adults. A meta-analysis was performed on anthropometric, cardiovascular and metabolic outcomes; Results: A total of 29 articles were retrieved including data from eight RCTs. All included RCTs were at low risk for performance bias related to objective outcomes. Collectively, articles included 704 subjects. Among the 334 subjects subjected to CR, the compliance with the intervention appeared generally high. Meta-analyses proved benefit of CR on reduction of body weight, BMI⁠, fat mass, total cholesterol, while a minor impact was shown for LDL, fasting glucose and insulin levels. No effect emerged for HDL and blood pressure after CR. Data were insufficient for other hormone variables in relation to meta-analysis of CR effects; Conclusion: CR is a nutritional pattern linked to improved cardiometabolic status. However, evidence is limited on the multidimensional aspects of health and requires more studies of high quality to identify the precise impact of CR on health status and longevity.

“Alternate Day Fasting Improves Physiological and Molecular Markers of Aging in Healthy, Non-obese Humans”

2019-stekovic.pdf: “Alternate Day Fasting Improves Physiological and Molecular Markers of Aging in Healthy, Non-obese Humans” (2019-09-03)

“Islam and Economic Performance: Historical and Contemporary Links”, Kuran 2018

“Islam and Economic Performance: Historical and Contemporary Links”⁠, Timur Kuran (2018; ⁠, ; backlinks; similar):

This essay critically evaluates the analytic literature concerned with causal connections between Islam and economic performance. It focuses on works since 1997, when this literature was last surveyed.

Among the findings are the following: Ramadan fasting by pregnant women harms prenatal development; Islamic charities mainly benefit the middle class; Islam affects educational outcomes less through Islamic schooling than through structural factors that handicap learning as a whole; Islamic finance hardly affects Muslim financial behavior; and low generalized trust depresses Muslim trade.

The last feature reflects the Muslim world’s delay in transitioning from personal to impersonal exchange. The delay resulted from the persistent simplicity of the private enterprises formed under Islamic law. Weak property rights reinforced the private sector’s stagnation by driving capital out of commerce and into rigid waqfs. Waqfs limited economic development through their inflexibility and democratization by restraining the development of civil society. Parts of the Muslim world conquered by Arab armies are especially undemocratic, which suggests that early Islamic institutions, including slave-based armies, were particularly critical to the persistence of authoritarian patterns of governance.

States have contributed themselves to the persistence of authoritarianism by treating Islam as an instrument of governance. As the world started to industrialize, non-Muslim subjects of Muslim-governed states pulled ahead of their Muslim neighbors by exercising the choice of law they enjoyed under Islamic law in favor of a Western legal system.

“Effects of Once-weekly Semaglutide on Appetite, Energy Intake, Control of Eating, Food Preference and Body Weight in Subjects With Obesity”, Blundell et al 2017

2017-blundell.pdf: “Effects of once-weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity”⁠, John Blundell, Graham Finlayson, Mads Axelsen, Anne Flint, Catherine Gibbons, Trine Kvist, Julie B. Hjerpsted et al (2017-03-07; ; similar):

Aim: The aim of this trial was to investigate the mechanism of action for body weight loss with semaglutide⁠.

Materials and methods: This randomised, double-blind, placebo-controlled, two-period crossover trial investigated the effects of 12 weeks of treatment with once-weekly subcutaneous semaglutide, dose-escalated to 1.0 mg, in 30 subjects with obesity. Ad libitum energy intake, ratings of appetite, thirst, nausea and well-being, control of eating, food preference, resting metabolic rate, body weight and body composition were assessed.

Results: After a standardised breakfast, semaglutide, compared with placebo, led to a lower ad libitum energy intake during lunch (−1255 kJ; p < 0.0001) and during the subsequent evening meal (p = 0.0401) and snacks (p = 0.0034), resulting in a 24% reduction in total energy intake across all ad libitum meals throughout the day (−3036 kJ; p < 0.0001). Fasting overall appetite suppression scores were improved with semaglutide vs placebo, while nausea ratings were similar. Semaglutide was associated with less hunger and food cravings, better control of eating and a lower preference for high-fat foods. Resting metabolic rate, adjusted for lean body mass, did not differ between treatments. Semaglutide led to a reduction from baseline in mean body weight of 5.0 kg, predominantly from body fat mass.

Conclusion: After 12 weeks of treatment, ad libitum energy intake was substantially lower with semaglutide vs placebo with a corresponding loss of body weight observed with semaglutide. In addition to reduced energy intake, likely mechanisms for semaglutide-induced weight loss included less appetite and food cravings, better control of eating and lower relative preference for fatty, energy-dense foods.

Video Abstract: A free Video Abstract to accompany this article is available⁠.

“Effect of Alternate-Day Fasting on Weight Loss, Weight Maintenance, and Cardioprotection Among Metabolically Healthy Obese AdultsA Randomized Clinical Trial”, Association 2017

2017-trepanowski.pdf: “Effect of Alternate-Day Fasting on Weight Loss, Weight Maintenance, and Cardioprotection Among Metabolically Healthy Obese AdultsA Randomized Clinical Trial”⁠, American Medical Association (2017-01-01)

“Intermittent Fasting Promotes White Adipose Browning and Decreases Obesity by Shaping the Gut Microbiota”, Li et al 2017

2017-li.pdf: “Intermittent Fasting Promotes White Adipose Browning and Decreases Obesity by Shaping the Gut Microbiota”⁠, Guolin Li, Cen Xie, Siyu Lu, Robert G. Nichols, Yuan Tian, Licen Li, Daxeshkumar Patel, Yinyan Ma, Chad N. Brocker et al (2017-01-01; )

“Time-restricted Feeding in Young Men Performing Resistance Training: A Randomized Controlled Trial”, Tinsley et al 2016

2016-tinsley.pdf: “Time-restricted feeding in young men performing resistance training: A randomized controlled trial”⁠, Grant M. Tinsley, Jeffrey S. Forsse, Natalie K. Butler, Antonio Paoli, Annie A. Bane, Paul M. La Bounty et al (2016-08-22; ; similar):

A randomized controlled trial was conducted to examine 8 weeks of resistance training (RT) with and without time-restricted feeding (TRF) in order to assess nutrient intake and changes in body composition and muscular strength in young recreationally active males.

The TRF programme consisted of consuming all calories within a 4-hour period of time for 4 days per week, but included no limitations on quantities or types of foods consumed. The RT programme was performed 3 days per week and consisted of alternating upper and lower body workouts. For each exercise, 4 sets leading to muscular failure between 8 and 12 repetitions were employed. Research visits were conducted at baseline, 4, and 8 weeks after study commencement. Measurements of total body composition by dual-energy X-ray absorptiometry and muscle cross-sectional area by ultrasound were obtained. Upper and lower body strength and endurance were assessed, and 4-day dietary records were collected.

TRF reduced energy intake by ~650 kcal per day of TRF, but did not affect total body composition within the duration of the study. Cross-sectional area of the biceps brachii and rectus femoris increased in both groups. Effect size data indicate a gain in lean soft tissue in the group that performed RT without TRF (+2.3 kg, d = 0.25). Upper and lower body strength and lower body muscular endurance increased in both groups, but effect sizes demonstrate greater improvements in the TRF group.

Overall, TRF reduced energy intake and did not adversely affect lean mass retention or muscular improvements with short-term RT in young males.

[Keywords: Intermittent fasting, time-restricted feeding, body composition, resistance training, muscular strength, energy intake]

“A Periodic Diet That Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan”, Brandhorst et al 2015

2015-brandhorst.pdf: “A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan”⁠, Sebastian Brandhorst, In Young Choi, Min Wei, Chia Wei Cheng, Sargis Sedrakyan, Gerardo Navarrete, Louis Dubeau et al (2015-01-01; backlinks)

“Efficacy of Fasting Calorie Restriction on Quality of Life among Aging Men”, Teng et al 2011

2011-teng.pdf: “Efficacy of fasting calorie restriction on quality of life among aging men”⁠, Nur Islami Mohd Fahmi Teng, Suzana Shahar, Zahara Abdul Manaf, Sai Krupa Das, Che Suhaili Che Taha, Wan Zurinah Wan Ngah et al (2011-10-24; backlinks)

“Extension of Lifespan in C. Elegans by Naphthoquinones That Act through Stress Hormesis Mechanisms”, Hunt et al 2011

“Extension of Lifespan in C. elegans by Naphthoquinones That Act through Stress Hormesis Mechanisms”⁠, Piper R. Hunt, Tae Gen Son, Mark A. Wilson, Quian-Sheng Yu, William H. Wood, Yongqing Zhang, Kevin G. Becker et al (2011-06-09; backlinks; similar):

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-1-dependent 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.

“Adaptations to Skeletal Muscle With Endurance Exercise Training in the Acutely Fed versus Overnight-fasted State”, Stannard et al 2010

2010-stannard.pdf: “Adaptations to skeletal muscle with endurance exercise training in the acutely fed versus overnight-fasted state”⁠, Stephen R. Stannard, Alex J. Buckley, Johann A. Edge, Martin W. Thompson (2010-07-01; backlinks)

“Alternate Day Calorie Restriction Improves Clinical Findings and Reduces Markers of Oxidative Stress and Inflammation in Overweight Adults With Moderate Asthma.”, Johnson et al 2007

“Alternate day calorie restriction improves clinical findings and reduces markers of oxidative stress and inflammation in overweight adults with moderate asthma.”⁠, Johnson, James B. Summer, Warren Cutler, Roy G. Martin, Bronwen Hyun, Dong-Hoon Dixit, Vishwa D. Pearson et al (2007-03-01; backlinks; similar):

Background: Asthma is an increasingly common disorder responsible for considerable morbidity and mortality. Although obesity is a risk factor for asthma and weight loss can improve symptoms, many patients do not adhere to low calorie diets and the impact of dietary restriction on the disease process is unknown.

Objective: 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.

Methods: 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 post bronchodilator spirometry was obtained at baseline and 8 weeks.

Results: 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 statistically-significantly, and PEF increased statistically-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 towards 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 statistically-significantly decreased by ADCR.

Conclusions: Compliance with the ADCR diet was high, symptoms and pulmonary function improved, and oxidative stress and inflammation declined in response to the dietary intervention. These findings demonstrate rapid and sustained beneficial effects of ADCR on the underlying disease process in subjects with asthma, suggesting a novel approach for therapeutic intervention in this disorder.

[Keywords: AQLQ, isoprostanes, peak expiratory flow, protein carbonyls, nitrotyrosine, BDNF, spirometry, tumor necrosis factor, oxidative stress]

“Metabolic Responses to Exercise After Fasting”, Dohm et al 1986

1986-dohm.pdf: “Metabolic responses to exercise after fasting”⁠, G. Lynis Dohm, Richard T. Beeker, Richard G. Israel, Edward B. Tapscott (1986-10-01; backlinks; similar):

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 statistically-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. Homeostasis is probably maintained as a result of increased gluconeogenesis and decreased utilization of glucose in the muscle as a result of lowered pyruvate dehydrogenase activity.

“Features of a Successful Therapeutic Fast of 382 Days’ Duration”, Fleming 1973

“Features of a successful therapeutic fast of 382 days’ duration”⁠, Stewart & Fleming (1973-03-01; similar):

A 27-year-old male patient fasted under supervision for 382 days and has subsequently maintained his normal weight. Blood glucose concentrations around 30 mg/​100 ml were recorded consistently during the last 8 months, although the patient was ambulant and attending as an out-patient. Responses to glucose and tolbutamide tolerance tests remained normal. The hyperglycaemic response to glucagon was reduced and latterly absent, but promptly returned to normal during carbohydrate refeeding. After an initial decrease was corrected, plasma potassium levels remained normal without supplementation. A temporary period of hypercalcaemia occurred towards the end of the fast. Decreased plasma magnesium concentrations were a consistent feature from the first month onwards. After 100 days of fasting there was a marked and persistent increase in the excretion of urinary cations and inorganic phosphate, which until then had been minimal. These increases may be due to dissolution of excessive soft tissue and skeletal mass. Prolonged fasting in this patient had no ill-effects.

…During the 382 days of the fast, the patient’s weight decreased from 456 to 180lb. 5 years after undertaking the fast, Mr A.B.’s weight remains around 196lb…The amount of weight lost and the rate of loss were not strikingly different from that of an earlier patient (Stewart, Fleming & Robertson, 1966) who reduced his weight from 432 to 235lb during 350 days of intermittent starvation.

…We wish to express our gratitude to Mr A. B. for his cheerful cooperation and steadfast application to the task of achieving a normal physique.

“Arctic Survival Rations. VI. The Physiological Effects of Restricted Diets During Successive Winter Field Trials”, Vaughan et al 1959

1959-vaughan.pdf: “Arctic Survival Rations. VI. The Physiological Effects of Restricted Diets During Successive Winter Field Trials”⁠, David A. Vaughan, Horace F. Drury, John P. Hannon, Lucile N. Vaughan, Anna M. Larson (1959-08-01; ; similar):

2 out of 3 different 1000 calorie combinations of pemmican and sugar were fed to each of 12 subjects during a two-phase, winter field study. All of the diets tested consisted primarily of pemmican, with the sugar contribution ranging from 0 to not more than 32% of the calories. The 5-day experimental phases were separated by a 7-day “recovery period.”

In both periods, on all diets, performance was considered adequate for survival situations involving moderate activity, thus confirming a previous report. The isocaloric substitution of pemmican with 40 grams of sugar raised the fasting blood sugar levels, decreased the nitrogen balance, and, in some cases, reduced ketonuria. However, a further increase in the proportion of sugar in the ration to 80 grams had no additional effect.

In the second period, the magnitude of all the above responses was strikingly reduced. In most cases, the degree of reduction did not appear to be related to differences in the composition of the Period I diets. The fasting blood sugars during the second period, however, did bear an inverse and highly statistically-significant relationship to the levels of carbohydrate intake during the first period. Thus, the data suggest that the adaptation to caloric restriction which developed during the first period, as evidenced by sequential changes in blood sugar levels, nitrogen balance and ketone body excretion, persisted throughout the recovery period, permitting the subjects to respond more favorably to the second dietary stress.

Minnesota Starvation Experiment


Intermittent fasting




Calorie restriction