Studies related to Dry Fasting, Water Fasting, Autophagy, and Autoimmune Diseases

Studies related to Dry Fasting, Water Fasting, Autophagy, and Autoimmune Diseases

Studies and books recommended to read when putting the pieces together.

Studies and books which are recommended to read when putting the pieces together. If this information is helpful to you, consider subscribing to help maintain the site.

Literature focused specifically on dry fasting

Dry Fasting 20 Questions & Answers

The original holy grail of dry fasting. The most important dry fasting book you can buy. Filonov pioneered dry fasting in 'The West' by making it accessible from Russia. Russian doctors have been dry fasting for a long time, with greats such as Leonid Schennikov pioneering the way.
Click Here to Buy on Amazon

The Phoenix Protocol

Dunning is specific that his intention with this is to encourage deep healing, stem cell release, mental clarity with a goal of extending your ability to live a healthy active life. Not just live longer, but live longer in a "younger" body.
Where the protocol kicks in differently than a standard dry fast is upon breaking the fast. He has a very specific refeeding procedure that includes supplements to encourage cleaning out of senescent cells and promoting stem cell release. He has a YouTube channel that shows some of his dry fasts day by day and describes the protocol in more depth. I suggest watching them before buying the book. If it looks like your thing, get the book. It's a solid resource on dry fasting, in my opinion.
Click Here to Buy on Amazon

Research focused specifically on dry fasting

Increased fat catabolism sustains water balance during fasting in zebra finches

When zebra finches fast, their body reacts differently based on their access to water. In a study, three groups were observed: birds with access to both food and water, birds without food but with water, and birds without both. It was expected, based on past research, that birds without food would use more proteins to maintain their water balance. However, the study found that birds without access to water relied more on burning fat, which produced six times more water for the body compared to those with water access. So, it seems that in these conditions, fat is the main source of water production in the body. The earlier belief that proteins were mainly used for this purpose might only apply when there's no fat left or when there's a high demand for energy.

Role of Dehydration in Heat Stress-Induced Variations in Mental Performance

Variation in mental performance under different levels of heat stress-induced dehydration was recorded in 11 subjects heat acclimatized to the tropicals. Dehydration was induced by a combination of water restriction and exercise in heat. The psychological functions--arithmetic ability, short-term memory, and visuomotor tracking--were assessed in a thermoneutral room after the subjects recovered fully from the effects of exercise in heat, as reflected by their oral temperature and heart rate. The results indicated significant deterioration in mental functions at 2% or more body dehydration levels. [Correlation to Glycerol benefits as an osmolyte for endurance sports but not dry fasting]

The role of human photosynthesis in predictive, preventive and personalized medicine

Downregulation of Klotho expression by dehydration - PubMed
Klotho, a transmembrane protein, protease, and hormone mainly expressed in renal tissue counteracts aging. Overexpression of Klotho substantially prolongs the life span. Klotho deficiency leads to excessive formation of 1,25(OH)(2)D(3), growth deficit, accelerated aging, and early death. Aging is fr …
Differential effects of fasting and dehydration in the pathogenesis of diabetic ketoacidosis - PubMed
Glycemia varies widely in patients with diabetic ketoacidosis (DKA), with plasma glucose concentrations between 10 to 50 mmol/L commonly encountered. The mechanism of this glycemic variability is uncertain. Our study examined the differential effects of fasting and dehydration on hyperglycemia induc …


The living organisms’ use the water as a universal solvent and it can participates in the chemical reactions and emerged from others reactions. The part of water which was formed during the process of cellular metabolism is considered to be metabolic water. There are several ways in which it may be formed: one of them through H+ HO- withdrawing from the same or different substances and interaction of protons and electrons with molecular oxygen (in the respiratory chain). The purpose of work is assessment of quantitative and qualitative of the metabolic water formed by oxidation of the main power substrate in the organism. The ways of using new formed water also will be considered.

The ‘selfish brain’ is regulated by aquaporins and autophagy under nutrient deprivation

The brain maintains its mass and physiological functional capacity compared with other organs under harsh conditions such as starvation, a mechanism termed the ‘selfish brain’ theory. To further investigate this phenomenon, mice were examined following water and/or food deprivation. Although the body weights of the mice, the weight of the organs except the brain and blood glucose levels were significantly reduced in the absence of water and/or food, the brain weight maintained its original state. Furthermore, no significant differences in the water content of the brain or its energy balance were observed when the mice were subjected to water and/or food deprivation. To further investigate the mechanism underlying the brain maintenance of water and substance homeostasis, the expression levels of aquaporins (AQPs) and autophagy‑specific protein long‑chain protein 3 (LC3) were examined. During the process of water and food deprivation, no significant differences in the transcriptional levels of AQPs were observed. However, autophagy activity levels were initially stimulated, then suppressed in a time‑dependent manner. LC3 and AQPs have important roles for the survival of the brain under conditions of food and water deprivation, which provided further understanding of the mechanism underlying the ‘selfish brain’ phenomenon. Although not involved in the energy regulation of the ‘selfish brain’, AQPs were observed to have important roles in water and food deprivation, specifically with regards to the control of water content. Additionally, the brain exhibits an ‘unselfish strategy’ using autophagy during water and/or food deprivation. The present study furthered current understanding of the ‘selfish brain’ theory, and identified additional regulating target genes of AQPs and autophagy, with the aim of providing a basis for the prevention of nutrient shortage in humans and animals.

Increased salt consumption induces body water conservation and decreases fluid intake

A 6-g/d increase in salt intake increased urine osmolyte excretion, but reduced free-water clearance, indicating endogenous free water accrual by urine concentration. The resulting endogenous water surplus reduced fluid intake at the 12-g/d salt intake level. Across all 3 levels of salt intake, half-weekly and weekly rhythmical mineralocorticoid release promoted free water reabsorption via the renal concentration mechanism. Mineralocorticoid-coupled increases in free water reabsorption were counterbalanced by rhythmical glucocorticoid release, with excretion of endogenous osmolyte and water surplus by relative urine dilution. A 6-g/d increase in salt intake decreased the level of rhythmical mineralocorticoid release and elevated rhythmical glucocorticoid release. The projected effect of salt-driven hormone rhythm modulation corresponded well with the measured decrease in water intake and an increase in urine volume with surplus osmolyte excretion

Intermittent drinking, oxytocin and human health

Looking at a waterhole, it is surprising that so many animals share the same space without visible signs of anxiety or aggression. Although waterholes are the preferred feeding locations of large carnivores, waterholes are shared by all type of herbivores of all sizes and shapes, including elephants. Recent research shows that the homeostatic disturbances leading to the "thirst feeling" not only activate specific substances regulating water and mineral household, but also the "trust and love" hormone oxytocin, while decreasing the production of the typical stress hormone cortisol. People using drugs, seem to be in search for oxytocin, as evidenced in studies with individuals on drugs such as ecstasy and gamma-hydroxybyturate. Hot environment, drought and increased sweating also activate specific oxytocin-producing parts of the hypothalamus, just as breastfeeding does in mother and infant. Water homeostasis is the only allostatic system activating trust neuro-anatomy and we suggest that this is due to the fact that all animals depend on water, whereas food type is species specific. Our hypothesis; regulating drinking behaviour through intermittent bulk drinking could increase oxytocin signalling, recover human trust and increase health by down-regulation of stress axis activity and inflammatory activity of the immune system. Intermittent bulk drinking should be defined as water (including tea and coffee) drinking up to a feeling of satiety and regulated by a mild feeling of thirst. This would mean that people would not drink less quantity but less frequently and that's how all animals, but also human newborns behave. It is the latter group, which is probably the only group of humans with a normal fluid homeostasis.

Growth hormone and fluid retention

A major side effect of growth hormone (GH) administration is fluid retention. Most data indicate that adult GH-deficient patients are dehydrated, i.e. they have low total body water, low extracellular water and low plasma volume. When GH substitution is initiated in these patients their body fluid compartments are restored to normal. The fluid retaining capacity of GH should therefore be regarded as a desirable physiological normalization of fluid homeostasis rather than an unpleasant side effect.

The Effects of Fasting During Ramadan on the Concentration of Serotonin, Dopamine, Brain-Derived Neurotrophic Factor and Nerve Growth Factor

Neurotransmitters and neurotrophic factors are signaling molecules that play a crucial role in cell proliferation, differentiation, survival and functions of neurons. It is believed that caloric restriction could help the health of the nervous system by affecting the synthesis of neurotrophins and neurotransmitter and oxygen radical metabolism. The objective was to investigate the plasma levels of serotonin, dopamine, brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF) in 29 healthy fasted subjects (22 women and 7 men) during the month of fasting in Ramadan. The levels of these factors were measured (using ELISA method) three times, 2 days before the fasting month as a control, on the 14th and 29th day of Ramadan as test groups. In addition, these factors were investigated in the group of women only. According to our investigation, the plasma levels of serotonin, BDNF and NGF were significantly increased during fasting month of Ramadan. In detail, the levels of these factors were increased in 14th and 29th day test groups compared to controls (P<0.05). Moreover, these levels were significantly increased on the 29th day compared to the 14th day test groups, but there were no differences between dopamine levels in all groups. Furthermore, the results obtained in women's groups were the same as those obtained in previous groups. Our findings suggest that plasma levels of serotonin, BDNF and NGF were significantly increased during fasting month of Ramadan.

Kinetics of osmotic stress regulate a cell fate switch of cell survival

Exposure of cells to diverse types of stressful environments differentially regulates cell fate. Although many types of stresses causing this differential regulation are known, it is unknown how changes over time of the same stressor regulate cell fate. Changes in extracellular osmolarity are critically involved in physiological and pathophysiological processes in several tissues. We observe that human cells survive gradual but not acute hyperosmotic stress. We find that stress, caspase, and apoptosis signaling do not activate during gradual stress in contrast to acute treatments. Contrary to the current paradigm, we see a substantial accumulation of proline in cells treated with gradual but not acute stresses. We show that proline can protect cells from hyperosmotic stress similar to the osmoprotection in plants and bacteria. Our studies found a cell fate switch that enables cells to survive gradually changing stress environments by preventing caspase activation and protect cells through proline accumulation.

Structured Water and Cancer: Orthomolecular Hydration Therapy

Hyperosmolarity increases EZ (structured) water inside the cell, which in turn promotes apoptosis.

It is a common practice to envision cancer exclusively as a genetic disease, however, in our perspective, changes in gene expression leading to malignancy are secondary to biochemical disturbances and at its core we consider cancer as a metabolic energetic disease. In this regard, incongruence with the concept of the bioenergetic theory of carcinogenesis, we propose structured water (EZ water), as an element that facilitates the correction of the fundamental energy disruption and the reestablishment of health. The prime approach for this therapy would be to infuse kosmotropic osmolytes by the intravenous route to improve the physiological conditions and promote the reduction of cancer growth with no side effects. By doing so, we could expect that the cells will regain their communication ability with a functioning Ras and p53 proteins and other metabolic and transcription factors. The end goal is to support the cell in overcoming its low-energy anaerobic glycolytic metabolism that favors uncontrolled growth and regain the full energetic potential of oxidative phosphorylation that supports controlled cell division and differentiation. To achieve this goal, we propose the use of metabolic correction to improve the membrane function of the mitochondria. The use of precursors, enzymatic cofactors, and a variety of biological response modifiers which includes structured water and its kosmotropic properties in enzyme dynamics are part of the metabolic correction concept.

Hyperosmotic Stress Induces Unconventional Autophagy Independent of the Ulk1 Complex

Autophagy is considered an adaptive mechanism against hyperosmotic stress. Although the process has been reported to be triggered by the inhibition of mTORC1, the precise downstream mechanisms remain elusive. Here, we demonstrate that hyperosmotic-stress-induced autophagy is different from conventional macroautophagy in mouse embryonic fibroblasts (MEFs) and human T24 cells.

Notes: The discovery that hyperosmotic stress can induce a form of autophagy independent of the Ulk1 complex is significant. Typically, Ulk1 is crucial for initiating autophagy during starvation. This suggests that there are alternative pathways to activate autophagy, which could be relevant to fasting. During fasting, the body undergoes various forms of stress, and this research indicates that autophagy can be triggered through mechanisms other than the conventional starvation pathway.

Osmotic stress-induced remodeling of the cortical cytoskeleton - PubMed
Osmotic stress is known to affect the cytoskeleton; however, this adaptive response has remained poorly characterized, and the underlying signaling pathways are unexplored. Here we show that hypertonicity induces submembranous de novo F-actin assembly concomitant with the peripheral translocation an …
Physiology of cell volume regulation in vertebrates - PubMed
The ability to control cell volume is pivotal for cell function. Cell volume perturbation elicits a wide array of signaling events, leading to protective (e.g., cytoskeletal rearrangement) and adaptive (e.g., altered expression of osmolyte transporters and heat shock proteins) measures and, in most …
Osmotic Stress Inhibits Proteasome by p38 MAPK-dependent Phosphorylation
Osmotic stress causes profound perturbations of cell functions. Although the adaptive responses required for cell survival upon osmotic stress are being unraveled, little is known about the effects of osmotic stress on ubiquitin-dependent proteolysis.…
Hypertonic stress induces rapid and widespread protein damage in C. elegans
Proteostasis is defined as the homeostatic mechanisms that maintain the function of all cytoplasmic proteins. We recently demonstrated that the capacity of the proteostasis network is a critical factor that defines the limits of cellular and organismal…
Ammonia-induced autophagy is independent of ULK1/ULK2 kinases
Autophagy, a lysosome-mediated catabolic process, contributes to maintenance of intracellular homeostasis and cellular response to metabolic stress. In yeast, genes essential to the execution of autophagy have been defined, including autophagy-related…

Potential Synergies of β-Hydroxybutyrate and Butyrate on the Modulation of Metabolism, Inflammation, Cognition, and General Health

The ketogenic diet, which is a high-fat, low-carb diet, has been used for years to treat conditions like weight issues, epilepsy, cancer, and even dementia. However, there are concerns about its safety because of increased ketone levels and lack of dietary fiber. Many people find it hard to follow due to its strict rules and initial side effects. Research shows that using external ketones and related supplements can be beneficial and might make the diet easier or even serve as an alternative. One such supplement combination is BHB and BA, which work well together at the cellular level.

What is ketosis and why do humans enter it? An introduction to the evolutionary biology of ketosis, fasting, and the ketogenic diet.

Hypertonic stress response

The cells in the inner part of a mammal's kidney are regularly exposed to very high levels of salt (NaCl). Surprisingly, even though this high salt concentration damages their DNA and interferes with the repair process, these cells continue to live and function properly both inside the body and in lab experiments. Researchers have found that these cells adapt to the stressful conditions by accumulating special substances that help them maintain their normal size and internal balance, despite the high salt levels.

However, these adaptations don't stop the DNA damage. The cells still experience DNA breaks, but these breaks get quickly fixed if the salt levels are reduced. Interestingly, the cells continue to grow and function well despite the ongoing DNA damage. Even though high salt levels mess with some of the typical responses to DNA damage, other elements involved in DNA repair still get activated.

So, the big questions are: How does the high salt concentration cause DNA breaks, and how do the cells manage to survive and function despite this damage? Scientists are still trying to figure this out. Can these adaptations be one of the mechanisms that help us rebound with health after a dry fast? It would stipulate that being in a hypertonic stress for too long would be dangerous, but controlled stresses seem to cause no problems and in fact the rebound infact seems healthy.

Hypertonic stress promotes autophagy and microtubule-dependent autophagosomal clusters

this study looks at how cells cope with changes in their environment that affect the balance of water and salt, a state known as "osmotic homeostasis." When cells are exposed to a high-salt environment (hypertonic stress), it can cause damage to their proteins. The study examines two specific things: autophagy, a process where cells "clean up" damaged parts, and the arrangement of microtubules, a component of the cell's skeleton.

The researchers found that when cells are stressed by high salt levels, they quickly start the autophagy process to degrade long-lasting proteins and generate other markers indicative of autophagy. Specific substances that affect the autophagy process showed that it is actively ongoing during this high-salt stress and is important for cell survival.

In addition to autophagy, high salt levels also rapidly change the organization of microtubules within the cells. These changes appear to help cluster special structures called autolysosomes near the cell's center, which seems to be a part of the autophagy process. This clustering and effective autophagy depend on the proper arrangement of these microtubules and are also influenced by other molecular mechanisms.

The study suggests that both autophagy and the reorganization of microtubules are crucial ways that cells protect themselves when exposed to high-salt conditions. With improved microtubules following a dry fast, we can expect the body to have improved autophagy pathways.

Evolution of water conservation in humans

Starvation in man

Very detailed, amazing paper on the effects of fasting from 1970s. You will need to find the PDF in a free full version which can be found in certain places. I have the PDF but cannot remember where I got it.

Dry Fasting Physiology: Responses to Hypovolemia and Hypertonicity

This study looked at the effects of dry fasting (no food or water) for 5 days on ten participants. The researchers measured a range of factors including hormones, blood and urine markers, and body measurements daily.


  • Certain hormones and markers related to stress, hydration, and inflammation increased significantly.
  • Measures of urine concentration and other markers in the blood also rose.
  • Waist circumference and body weight dropped noticeably.
  • Levels of some hormones and markers related to red blood cell production and sodium excretion decreased.
  • Vitamin C levels decreased over time.
  • More than half of the weight loss came from urine, followed by water loss through breathing and skin, then a small amount from stool and respiratory gases.

Dry fasting had a range of effects on the body, such as increased stress hormones, improved antioxidant capacity, and changes in blood and urine markers. The study suggests that dry fasting may have short-term benefits like anti-inflammatory and immune-boosting effects and could potentially be useful for treating conditions like edema (swelling), obesity, and certain inflammatory and blood-flow related diseases. Since this was a very simple study, but one of the most direct dry fasting related ones, we can extrapolate that dry fasting will work for a lot of inflammatory diseases, which is one of the core features of autoimmune issues that cause system-wide inflammation.

Vasopressin increases human risky cooperative behavior

Dry fasting literally improves connection and bonding between humans. Altruistic and emotional intelligence improvement.

Glucose-induced alkalosis in fasting subjects

This study documents the development of alkalosis in patients returning to caloric intake after a period of starvation and investigates the mechanisms responsible for this metabolic alteration. We studied the acid-base status, bicarbonate reabsorption, acid excretion, and sodium metabolism during fasting and glucose refeeding in 19 patients receiving sodium supplements.

Metabolic alkalosis developed promptly in all of the subjects who terminated an 18 day fast with 300 g of glucose daily for 4 days. Tubular maximum reabsorptive capacity for bicarbonate and renal bicarbonate threshold determinations were performed at varying intervals in six and seven subjects, respectively, who had fasted for 3-18 days. The results demonstrated that bicarbonate reabsorptive capacity was normal or low during early fasting, markedly elevated during the 2nd wk; and moderately elevated during the 3rd wk of fasting. Glucose administration at all stages of fasting caused a further increase in bicarbonate threshold.

Sodium balance during fasting with sodium supplements was found to follow a triphasic pattern, with the occurrence of a natriuresis during the 1st wk followed by a period of sodium retention after which neutral daily sodium balance was reestablished. Correlation of bicarbonate reabsorption with sodium homeostasis indicated a slight decrease in renal bicarbonate threshold during the natriuretic phase, a marked increase in bicarbonate reabsorption during the period of sodium retention, and a continued moderate elevation of threshold after sodium balance was reestablished. This relationship was interpreted to indicate that changes in bicarbonate reabsorption during fasting and refeeding may be secondary to alterations in the renal reabsorption of sodium.

Dawn-to-dusk dry fasting induces anti-atherosclerotic, anti-inflammatory, and anti-tumorigenic proteome in peripheral blood mononuclear cells in subjects with metabolic syndrome

In a study focusing on metabolic syndrome—a condition linked to inflammation and higher heart disease risk—we found that fasting from dawn to dusk for 4 weeks brought about positive changes in blood cell proteins. Among 14 participants who fasted for over 14 hours daily, we observed a significant decrease in proteins tied to heart disease and notable shifts in genes related to fat metabolism. Simply put, this fasting method might help mitigate vascular issues by introducing beneficial cellular changes.

Effects of Ramadan and Non-ramadan Intermittent Fasting on Gut Microbiome

Twenty-eight studies were selected after screening. Some of the studies were performed on animal models and some on humans. The results of these studies indicate a significant shift in the gut microbiota, especially an increase in the abundance of Lactobacillus and Bifidobacteria following fasting diets. The results of some studies also showed an increase in the bacterial diversity, decrease inflammation and increased production of some metabolites such as short-chain fatty acids (SCFAs) in individuals or samples under fasting diets. Moreover, Ramadan fasting, as a kind of IF, improves health parameters through positive effects on some bacterial strains such as Akkermansia muciniphila and Bacteroide.

Autophagy Research Relating to Dry Fasting

Translocation and clustering of endosomes and lysosomes depends on microtubules

Indirect immunofluorescence labeling of normal rat kidney (NRK) cells with antibodies recognizing a lysosomal glycoprotein (LGP 120; Lewis, V., S.A. Green, M. Marsh, P. Vihko, A. Helenius, and I. Mellman, 1985, J. Cell Biol., 100:1839-1847) reveals that lysosomes accumulate in the region around the microtubule-organizing center (MTOC). This clustering of lysosomes depends on microtubules. When the interphase microtubules are depolymerized by treatment of the cells with nocodazole or during mitosis, the lysosomes disperse throughout the cytoplasm. Lysosomes recluster rapidly (within 30-60 min) in the region of the centrosomes either upon removal of the drug, or, in telophase, when repolymerization of interphase microtubules has occurred. During this translocation process the lysosomes can be found aligned along centrosomal microtubules. Endosomes and lysosomes can be visualized by incubating living cells with acridine orange. We have analyzed the movement of these labeled endocytic organelles in vivo by video-enhanced fluorescence microscopy. Translocation of endosomes and lysosomes occurs along linear tracks (up to 10 microns long) by discontinuous saltations (with velocities of up to 2.5 microns/s). Organelles move bidirectionally with respect to the MTOC. This movement ceases when microtubules are depolymerized by treatment of the cells with nocodazole. After nocodazole washout and microtubule repolymerization, the translocation and reclustering of fluorescent organelles predominantly occurs in a unidirectional manner towards the area of the MTOC. Organelle movement remains unaffected when cells are treated with cytochalasin D, or when the collapse of intermediate filaments is induced by microinjected monoclonal antivimentin antibodies. It can be concluded that translocation of endosomes and lysosomes occurs along microtubules and is independent of the intermediate filament and microfilament networks. Microrubule requiredment with inmproved autophagy, fixed through dry fasting/hyperosmotic stress.

Ketone Bodies Stimulate Chaperone-mediated Autophagy

Autophagy induction contributes to the neuroprotective effect of intermittent fasting in experimental spinal cord injury

We found remarkable improvement in the behavioral test in the IF group. Western blot revealed marked decrease of cleaved caspase-3 level as well as bax/bcl-2 ratio in the IF group, suggesting an inhibition of intrinsic apoptosis pathway. immunofluorescence further revealed more NeuN-positive cells in the IF group, revealing that IF preserved more neurons after acute SCI. In addition, the expression of autophagy markers like LC3-II and beclin 1 were also increased in the IF group compared to the ad libitum feeding group that underwent acute SCI, while p62, the substrate protein of autophagy, presented considerable decrease, suggesting an up regulation of autophagy by IF. Blocking autophagy with 3-MA, a selective inhibitor of autophagy, reversed the down regulated apoptosis-related markers by IF, further validating that the neuroprotective effect of IF was associated with autophagy enhancement.

Caffeine intake increases plasma ketones: an acute metabolic study in humans

Brain glucose uptake declines during aging and is significantly impaired in Alzheimer's disease. Ketones are the main alternative brain fuel to glucose so they represent a potential approach to compensate for the brain glucose reduction. Caffeine is of interest as a potential ketogenic agent owing to its actions on lipolysis and lipid oxidation but whether it is ketogenic in humans is unknown. This study aimed to evaluate the acute ketogenic effect of 2 doses of caffeine (2.5; 5.0 mg/kg) in 10 healthy adults. Caffeine given at breakfast significantly stimulated ketone production in a dose-dependent manner (+88%; +116%) and also raised plasma free fatty acids. Whether caffeine has long-term ketogenic effects or could enhance the ketogenic effect of medium chain triglycerides remains to be determined.

Autophagy in Alzheimer’s disease pathogenesis: Therapeutic potential and future perspectives

Alzheimer’s disease (AD) is a complex neurodegenerative disease in the elderly and the most common cause of human dementia. AD is characterized by accumulation of abnormal protein aggregates including amyloid plaques (composed of beta-amyloid (Aβ) peptides) and neurofibrillary tangles (formed by hyper-phosphorylated tau protein). Synaptic plasticity, neuroinflammation, calcium signaling etc. also show dysfunction in AD patients. Autophagy is an evolutionarily conserved lysosome-dependent cellular event in eukaryotes. It is closely linked to modulation of protein metabolism, through which damaged organelles and mis-folded proteins are degraded and then recycled to maintain protein homeostasis. Accumulating evidence has shown that impaired autophagy also contributes to AD pathogenesis. In the present review, we highlight the role of autophagy, including bulk and selective autophagy, in regulating metabolic circuits in AD pathogenesis. We also discuss the potential and future perspectives of autophagy-inducing strategies in AD therapeutics.

The ULK1 complex

The Atg1/ULK1 complex plays a central role in starvation-induced autophagy, integrating signals from upstream sensors such as MTOR and AMPK and transducing them to the downstream autophagy pathway. Much progress has been made in the last few years in understanding the mechanisms by which the complex is regulated through protein-protein interactions and post-translational modifications, providing insights into how the cell modulates autophagy, particularly in response to nutrient status. However, how the ULK1 complex transduces upstream signals to the downstream central autophagy pathway is still unclear. Although the protein kinase activity of ULK1 is required for its autophagic function, its protein substrate(s) responsible for autophagy activation has not been identified. Furthermore, examples of potential ULK1-independent autophagy have emerged, indicating that under certain specific contexts, the ULK1 complex might be dispensable for autophagy activation. This raises the question of how the autophagic machinery is activated independent of the ULK1 complex and what are the biological functions of such noncanonical autophagy pathways.

Effect of fasting on cancer: A narrative review of scientific evidence

Emerging evidence suggests that fasting could play a key role in cancer treatment by fostering conditions that limit cancer cells' adaptability, survival, and growth. Fasting could increase the effectiveness of cancer treatments and limit adverse events. Yet, we lack an integrated mechanistic model for how these two complicated systems interact, limiting our ability to understand, prevent, and treat cancer using fasting. Here, we review recent findings at the interface of oncology and fasting metabolism, with an emphasis on human clinical studies of intermittent fasting. We recommend combining prolonged periodic fasting with a standard conventional therapeutic approach to promote cancer-free survival, treatment efficacy and reduce side effects in cancer patients.

Fasting Enhances TRAIL-Mediated Liver Natural Killer Cell Activity via HSP70 Upregulation

In this study, researchers investigated how fasting affects the function of natural killer (NK) cells in mice. They found that after a 3-day fast, specific liver-resident NK cells increased the proportions of certain cell markers associated with enhanced cell function. Interestingly, NK cells transferred into fasted mice converted at higher rates into cells with improved function compared to those in fed mice. The study also revealed that liver NK cells showed increased antitumor activity following fasting. The researchers discovered elevated levels of heat shock protein 70 (HSP70) in the liver tissues of fasted mice, and experiments using this protein indicated that it played a role in activating NK cells. Overall, acute fasting seems to boost the effectiveness of liver NK cells against cancer cells by increasing the presence of HSP70 and enhancing specific cell markers, suggesting a potential benefit for immune function.

Additionally, it's hypothesized that NK cells don't require prior activation to exert their function against abnormal cells. While fasting has been observed to enhance NK cell activity against cancer cells, the molecular mechanisms behind this phenomenon were not fully understood. Few studies addressed whether this alteration in NK cell activity due to dietary changes has practical implications. It's known that NK cells use various mechanisms to control abnormal cells, including the release of cytolytic granules and death-inducing ligands like TRAIL. The researchers suggested that HSP70, elevated during fasting, might play a role in enhancing NK cell activity against cancer cells. This study provides insights into how fasting might influence immune function, particularly NK cell activity, against cancer cells.

Fasting is a physiological stimulus of vagus-mediated enhancement of nociception in the female rat

We wanted to understand how the vagus nerve, a nerve in your body, affects pain sensation and whether it's influenced by fasting. We did tests on female rats because they showed lower baseline activity in this nerve compared to males. After fasting for 48 hours, female rats experienced more pain in our tests, while fasting didn't affect pain in male rats. Cutting the subdiaphragmatic vagus nerve prevented this effect, showing the nerve was involved. In summary, fasting can activate a natural pain-modulating pathway involving the vagus nerve, particularly in females, and this may be related to changes in stomach activity.

Metabolomic Evidence for Peroxisomal Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Disrupted fatty acid metabolism. ME/CFS is a long-term illness marked by extreme fatigue, cognitive issues, sleep problems, and more. Often, its onset is similar to infections. In a study of blood samples from 106 ME/CFS patients and 91 healthy individuals, we noticed key differences in certain lipid and acid levels between the two groups. With these differences, we could identify ME/CFS patients with up to 87.3% accuracy using machine learning. This suggests a possible metabolic imbalance in ME/CFS patients, hinting at potential causes for the condition. This could also be a reason why so many severe sufferers suffer badly with their first fasts and believe they deteriorate. In this case you need to push fasting deeper to force the body to turn on the fatty acid/ketone metabolism.

Fasting as key tone for COVID immunity

The study highlights the role of the ketone body BHB (β-hydroxybutyrate) in strengthening the immune response, especially in the context of COVID-19. When individuals fast or undergo certain conditions, the body produces BHB as an alternative energy source, which also has signaling capabilities for immune cells. Interestingly, patients with severe COVID-19 showed reduced levels of BHB and weaker T cell functions. When these patients were given a diet or supplements to boost BHB, their T cells' ability to fight the virus improved, leading to better health outcomes. This BHB boost enhances mitochondrial function in the cells, improving their energy production and overall health. The study suggests BHB might be a potential treatment for severe COVID-19 and emphasizes the link between diet, metabolism, and immunity.

Fasting mitigates immediate hypersensitivity: a pivotal role of endogenous D-beta-hydroxybutyrate

Fasting, a type of dietary restriction, has numerous health benefits. When fasting, ketone bodies rise in the blood and act as alternative energy sources. This study explored the effects of fasting on hypersensitivity and the role of the ketone body D-beta-hydroxybutyrate in reducing immediate hypersensitivity reactions. Using a rat model for nasal allergies, we studied the outcomes of fasting and diets that elevate D-beta-hydroxybutyrate levels. The results showed that fasting effectively decreased hypersensitivity reactions. This reduction was linked to the stabilization of mast cells, cells central to hypersensitivity reactions, by elevated D-beta-hydroxybutyrate levels during fasting.

The effect of fasting on (Parasites) Ascaris suum and Oesophagostomum spp. in growing pigs

Experiments were conducted to study the possible influence of fasting on Ascaris suum and Oesophagostomum spp. in growing pigs. Forty young crossbred pigs naturally infected with A. suum and Oesophagostomum spp. were used. In one experiment 10 pigs were fasted and offered water ad libitum for 6 days, in another experiment for 10 days. Subsequently, these pigs, together with 10 non-fasted control pigs per experiment were slaughtered, and worm numbers, worm location, sex, developpmental stage and female worm fecundity were determined. Pigs fasted for 10 but not for 6 days had decreased numbers of A. suum and Oesophagostomum spp. at slaughter vs controls, and worms were found in more distal locations in the gastrointestinal tract. Fasting for both 6 and 10 days significantly lowered the fecundity of both worm species.

The Host Autophagy During Toxoplasma Infection (Parasites)

This study talks about how cells in our body use a process called autophagy to break down and reuse their parts. This helps fight off infections by trapping and destroying tiny invaders called parasites. But, some smart parasites like Toxoplasma gondii have figured out ways to dodge this process and even use it to grow, which can make people sick for a long time. The study looks at how our cells try to control this parasite using autophagy and how the parasite is clever enough to mess with this process to keep itself safe. It also explains how autophagy works, including special types like xenophagy and LC3-associated phagocytosis, and talks about how Toxoplasma gondii is usually stopped by autophagy but sometimes manages to slip away for its own good.

How a high-fat diet allows expulsion of intestinal parasite worms

Scientists have discovered that a high-fat diet allows the immune system to eliminate a parasitic worm which is a major cause of death and illness in the developing world. Parasitic worms affect up to a billion people, particularly in developing nations with poor sanitation. One of these parasites known as 'whipworm' can cause long lasting infections in the large intestine. Researchers have discovered that a high-fat diet allows the immune system to eliminate the parasite.

Chaperone-mediated autophagy and endosomal microautophagy: Jointed by a chaperoneTHEMATIC MINIREVIEW: Chaperones and selective autophagy

A variety of mechanisms deliver cytosolic materials to the lysosomal compartment for degradation through autophagy. Here, we focus on two autophagic pathways, the chaperone-mediated autophagy and the endosomal microautophagy that rely on the cytosolic chaperone hsc70 for substrate targeting. Although hsc70 participates in the triage of proteins for degradation by different proteolytic systems, the common characteristic shared by these two forms of autophagy is that hsc70 binds directly to a specific five-amino acid motif in the cargo protein for its autophagic targeting. We summarize the current understanding of the molecular machineries behind each of these types of autophagy.

Anti-aging and Fasting

Aging as a consequence of intracellular water volume and density

Aging is the result of a gradual failure of physiological and/or biochemical pathways that culminates with the death of the organism. Until now, the causative factors of aging are elusive, despite the increasing number of theories that try to explain how aging initiates. Interestingly, aging cells show an increase in intracellular water volume, but this fact is barely explored in aging studies. All cells have a crowded cytoplasm, where the high concentration and proximity of macromolecules create an environment that excludes many small molecules, including water. In this crowded environment, water can be found in two states termed low density water (LDW), which shows low reactivity and has an ice-like structure, and high density water (HDW) that has a disorganized structure and is highly reactive. LDW predominates in a macromolecular crowded environment, while HDW is found only in microenvironments within cytoplasm. In this sense, we hypothesized that the failure in the water homeostasis mechanisms with time changes the equilibrium between LDW and HDW, increasing the concentration of intracellular HDW. Being reactive, HDW leads to the generation of reactive oxygen species and disturbs the crowded cytoplasm environment, resulting in a diminished efficiency of metabolic reactions. Noteworthy, the cell becomes less prone to repair damage when the concentration of HDW increases with time, resulting in aging and finally death. Interestingly, some biological mechanisms (e.g., anhydrobiosis) reduce the concentration of intracellular water and prolong the life of cells and/or organisms. In this sense, anhydrobiosis and related biological mechanisms could be used as a platform to study new anti-aging therapies.

Fasting promotes the expression of SIRT1, an NAD+ -dependent protein deacetylase, via activation of PPARalpha in mice

Calorie restriction (CR) prolongs life in various species by increasing the NAD(+)/NADH ratio and activating SIRT1, a protein linked to lifespan. CR also influences peroxisome proliferator-activated receptors (PPARs) that regulate metabolic functions. This study explored how SIRT1 and PPARalpha work together in fasting-induced anti-aging pathways. Fasting for 24 hours in mice increased both SIRT1 and PPARalpha in the liver, with rising NAD(+) levels. In cell experiments, higher NAD(+) boosted SIRT1 and PPARalpha gene expression, while more NADH reduced them. This suggests that PPARalpha plays a key role upstream from SIRT1 in fasting-related anti-aging processes.

Prolonged Fasting reduces IGF-1/PKA to promote hematopoietic stem cell-based regeneration and reverse immunosuppression

Prolonged fasting (PF) lasting 48–120 hours reduces pro-growth signaling and activates pathways that enhance cellular resistance to toxins and stress in mice and humans. Defects in the immune system are linked to aging and many diseases. Our study shows that extended fasting decreases IGF-1 levels in the blood and PKA activity in certain cells. This change positively impacts long-term blood-forming stem cells, enhancing their resilience, self-renewal, and balanced regeneration. Regular fasting cycles can counteract the negative effects of chemotherapy and reverse certain age-related issues in mice. We also observed that reducing IGF-1 levels, which happens during fasting, plays a key role in protecting and rejuvenating these stem cells.
Cycles of prolonged fasting (PF) reduce damage in bone marrow stem and progenitor cells and protect mice against chemotoxicity

Fasting boosts stem cells’ regenerative capacity

As people age, their intestinal stem cells begin to lose their ability to regenerate. These stem cells are the source for all new intestinal cells, so this decline can make it more difficult to recover from gastrointestinal infections or other conditions that affect the intestine.

This age-related loss of stem cell function can be reversed by a 24-hour fast, according to a new study from MIT biologists. The researchers found that fasting dramatically improves stem cells’ ability to regenerate, in both aged and young mice.

In fasting mice, cells begin breaking down fatty acids instead of glucose, a change that stimulates the stem cells to become more regenerative. The researchers found that they could also boost regeneration with a molecule that activates the same metabolic switch. Such an intervention could potentially help older people recovering from GI infections or cancer patients undergoing chemotherapy, the researchers say.

Fasting for stem cell rejuvenation

Throughout history, humans have sought ways to enhance longevity and health. Among various anti-aging strategies, calorie-restricted diets and fasting are particularly effective, offering potential benefits like reduced disease risk and enhanced stem cell function. Planarians, organisms known for their remarkable regenerative abilities, can withstand long fasting periods and quickly regenerate once fed. Interestingly, their stem cells, constituting about 25% of their body, remain consistently robust and show no aging signs, making them "immortal." Our research indicates that fasting in planarians lengthens the telomeres of their stem cells, suggesting rejuvenation. This rejuvenation is linked to the down-regulation of mTOR signaling, a pathway that's also related to dietary restrictions. Despite reduced mTOR activity, telomeres elongate without changing the stem cells' division rates. This phenomenon might correlate with stem cell pluripotency, indicating that fasting could potentially boost pluripotency through mTOR modulation. This insight could significantly impact our understanding of regeneration and stem cell aging.

Fasting: The History, Pathophysiology and Complications

Growth Hormone increase 300% after 5 days wet, and 1250% by day 26, then it drops. Metabolically, early fasting is characterized by a high rate of gluconeogenesis with amino acids as the primary substrates. As fasting continues, progressive ketosis develops due to the mobilization and oxidation of fatty acids. As ketone levels rise they replace glucose as the primary energy source in the central nervous system, thereby decreasing the need for gluconeogenesis and sparing protein catabolism. Several hormonal changes occur during fasting, including a fall in insulin and T3 levels and a rise in glucagon and reverse T3 levels. Most studies of fasting have used obese persons and results may not always apply to lean persons. Medical complications seen in fasting include gout (please look into ketones and uric acid, there's a reason that gout flares up in ketosis, but you need to push through it, or prep by getting into a strict keto diet early before attempting fasting - yannick) and urate nephrolithiasis, postural hypotension, and cardiac arrhythmias.

Melatonin and Pathological Cell Interactions: Mitochondrial Glucose Processing in Cancer Cells

Melatonin is primarily made in the pineal gland at night, but it's also produced in small amounts by the mitochondria in other cells. This mitochondrial melatonin helps regulate glucose metabolism. In some unhealthy cells, like those with aerobic glycolysis, pyruvate can't get into the mitochondria, leading to a lack of acetyl-CoA, which is needed for melatonin production. When you add melatonin or get it from the pineal gland in these cells, it can improve their metabolism and allow pyruvate into the mitochondria, making them healthier.

Melatonin in Mitochondria: Mitigating Clear and Present Dangers

In cancer cells, glucose is primarily metabolized to pyruvate and then to lactate in the cytosol. By allowing the conversion of pyruvate to acetyl-CoA in mitochondria, melatonin reprograms glucose metabolism in cancer cells to a normal cell phenotype. Acetyl-CoA in the mitochondria also serves as a necessary co-factor for the rate-limiting enzyme in melatonin synthesis, thus ensuring melatonin production in mitochondria of normal cells.

Viral Reactivation, Ketosis relating to Long Covid/Lyme's/ME/CFS and Disease

Chronic fatigue disorders: an inappropriate response to arginine vasopressin? (ADH)

Chronic fatigue disorders are characterized by a subjectively defined group of symptoms such as chronic fatigue, mental confusion, exertional malaise, weight changes, and/or diffuse multi-joint pains. Significant clinical overlap exists between chronic fatigue disorders and the syndrome of serum inappropriate anti-diuretic hormone (SIADH). Both chronic fatigue disorders and SIADH are characterized by lethargy and mental confusion. Both disorders can be induced or exacerbated by viral illnesses, physical exertion, emotional stress and/or hypotension. Both can be treated with salt loading and glucocorticoids. Therefore, altered water metabolism resulting from inappropriate release and/or response to arginine vasopressin (AVP) is proposed as a pathophysiological basis of certain chronic fatigue disorders. Moreover, these data suggest that salt loading and/or direct inhibition of AVP may be an effective therapeutic approach in individuals with chronic fatigue disorders.

The impact of diurnal fasting during Ramadan on patients with chronic heart failure

The effects of fasting during Ramadan on stable patients with chronic heart failure are minimal. The majority of patients with stable cardiac disease can fast during Ramadan without significant detrimental effects.

Heart Rate Variability and Sympathetic Activity Is Modulated by Very Low-Calorie Ketogenic Diet

Obesity is linked to an imbalance in our energy and the buildup of visceral fat. Our body's systems control our appetite, metabolism, and energy consumption. The central nervous system oversees these processes, including the interaction between the sympathetic and parasympathetic nervous systems, which impacts heart rate variability (HRV). This study aimed to explore how two diets, a very low-calorie ketogenic diet (VLCKD) and a low-caloric diet (LCD), affect the nervous system's function, particularly HRV. 26 obese individuals tried these diets, with the VLCKD group showing more significant reductions in sympathetic nervous system activity, as seen in lower heart rates. This suggests that specific diets can influence our nervous system balance

Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41)

"On the other hand, a ketone body, β-hydroxybutyrate, produced during starvation or diabetes, suppressed SNS activity by antagonizing GPR41."

To keep our energy balanced, our bodies rely on glucose when well-fed and switch to ketone bodies during times like starvation. The sympathetic nervous system (SNS) controls this balance by adjusting energy expenditure based on our diet. While we know how glucose impacts this, the roles of short-chain fatty acids (SCFAs) and ketone bodies have been unclear. This study found that SCFAs and ketone bodies directly influence the SNS through a receptor called GPR41, which plays a key role in regulating energy expenditure. This discovery sheds light on how SCFAs and ketone bodies help our bodies maintain metabolic balance.

Tissue specific signature of HHV-6 infection in ME/CFS

Human herpesviruses (HHVs) like HHV-6, HCMV, and EBV typically don't lead to severe diseases upon first exposure, and many people might not even be aware they've been infected. These viruses establish a quiet, long-term presence in the body, known as latency. It's believed that periodic reactivation of these viruses in specific body regions may trigger certain diseases. For instance, HHV-6 has been linked to Alzheimer's Disease and Chronic Fatigue Syndrome (ME/CFS). Recent research, including our findings, showed active HHV-6 and EBV infections in specific areas of the brain and spinal cord exclusively in ME/CFS patients. Considering the similarities in post-viral symptoms between long COVID and ME/CFS, these findings open a pathway to exploring if herpesvirus reactivation might also play a role in long COVID's persistent symptoms.

Short-term intensive fasting enhances the immune function of red blood cells in humans

evaluate the impact of short-term intensive fasting (STIF), known as beego, on red blood cells by profiling the cells from the STIF subjects before and after 6 days of fasting and 6 days of gradual refeeding. We found that STIF, by triggering the activation of the complement system via the complement receptor on the membrane of red blood cells, boosts fairly sustainable function of red blood cells in immune responses in close relation to various pathogens, including viruses, bacteria and parasites, particularly with the pronounced capacity to defend against SARS-CoV-2, without compromising their oxygen delivery capacity and viability.

Meditation, Diabetes, Food, Insulin, and Fasting

Effects of Fasting and Refeeding. I. Studies on Sodium, Potassium and Water Excretion on a Constant Electrolyte and Fluid Intake

Seventeen subjects were maintained on a constant electrolyte and fluid intake during periods of equilibration, starvation and refeeding. During 3 days of fasting, a mean daily weight loss of 800 g was accompanied by progressive natriuresis and kaliuresis without increase in urine volume. The net amount of sodium excreted as a consequence of fasting was independent of the amount of sodium supplemented. Carbohydrate refeeding induces very rapid antidiuresis of sodium and potassium. Protein has a delayed action, while fat refeeding aggravates the negative sodium balance. The sodium retaining action of carbohydrate requires a pre-existing metabolic setting induced by starvation. Bicarbonate supplementation during fasting does not alter the pattern of sodium excretion. The data suggest that the sodium retaining action of carbohydrate after brief starvation is not secondary to aldosterone, glucocorticosteroids or changes in catecholamine levels.

Fasting induces a form of autonomic synaptic plasticity that prevents hypoglycemia

To prevent a fall in blood glucose during fasting, the counter-regulatory response is activated. An important component of this pathway involves the autonomic nervous system and release of epinephrine from the adrenal gland. This autonomic response is often referred to as a reflex, implying the output is hardwired and inflexible. Here we show the strength of the terminal synapse that controls epinephrine release is actually highly plastic. Fasting leads to a long-lasting increase in synaptic strength by a process that requires neuropeptide Y and Y5 receptors. In the absence of neuropeptide Y, synaptic strengthening is absent, epinephrine release is reduced, and the mice become hypoglycemic. These findings indicate that the response to fasting involves significant autonomic synaptic plasticity.

Ketosis with enhanced GABAergic tone promotes physiological changes in transcendental meditation

Transcendental meditation (TM) is a stylized form of physical and mental relaxation which is associated with changes in the secretion and release of several pituitary hormones. The hormonal changes induced by TM mimic the effects of the inhibitory neurotransmitter gamma aminobutyric acid (GABA). It is hypothesized that TM produces changes in pituitary hormone secretion by enhancing hypothalamic GABAergic tone as a result of TM associated ketosis. Ketosis enhances the entry of glutamate, the amino acid substrate of GABA into synaptosomes, making more glutamate available for conversion to GABA through the glutamate decarboxylase pathway.

Metabolic and EEG changes during transcendental meditation: an explanation

Two experiments were conducted to measure the oxygen uptake (Experiment II) and the carbon dioxide production (Experiment I) during transcendental meditation. A control group of non-meditators and a few meditators listening to music was used for both experiments. In Experiment I, a controlled group of fasting meditators was also included. A drop in oxygen consumption and carbon dioxide production, found by previous authors during transcendental meditation, was confirmed. It was, however, possible to show that these drops were physiologically of small significance, and were of the magnitude to be expected from muscle relaxation. EEG recordings were taken during Experiment II in the meditating group. The EEG results showed transcendental meditation to be a method of holding the mediator's level of consciousness at stage 'onset' sleep. No evidence could be found to suggest that meditation produced a hypometabolic state beyond that produced by muscle relaxation and there was no evidence that the EEG changes were different from those observed in stage 'onset' sleep. No support was found for the idea that transcendental meditation is a fourth stage of consciousness.

What is the importance of Stage 1 sleep?Stage 1, also called N1, is essentially when a person first falls asleep. This stage normally lasts just one to seven minutes. During N1 sleep, the body has not fully relaxed, though the body and brain activities start to slow with periods of brief movements.

Review of Controlled Research on the Transcendental Meditation Program and Cardiovascular Disease

Evidence for its ability to reduce traditional and novel risk factors for CVD includes: 1) decreases in blood pressure, 2) reduced use of tobacco and alcohol, 3) lowering of high cholesterol and lipid oxidation, and 4) decreased psychosocial stress. Changes expected to result from reducing these risk factors, namely, reversal of atherosclerosis, reduction of myocardial ischemia and left ventricular hypertrophy, reduced health insurance claims for CVD, and reduced mortality, also have been found with TM practice. Research on mechanisms suggests that some of the CVD-related benefits as a result of this technique could arise from normalization of neuroendocrine systems whose function has been distorted by chronic stress.

Chronic illness often leads to chronic stress. In the case of long covid, it's quite obvious that trauma (cytokine storm type) affects the nervous system resulting in destabilization and chronic sympathetic state activation. I no longer think meditation is optional but a requirement paired with fasting and nutritional changes. Fasting induces TM type state, so it is a shortcut while you rev up your meditation practices.

Calorie Restriction in Combination with GABA Ameliorates Type 2 Diabetes

Dysfunction of adipocytes and β-cells are crucial in the progression of obesity-related insulin resistance and type 2 diabetes (T2D). γ-Aminobutyric Acid (GABA) is a key neurotransmitter and is secreted by β-cells. It exerts protective and regenerative effects on β-cells. At the metabolic level, Calorie Restriction (CR) has been shown to improve insulin sensitivity, reduces Fasting Blood Glucose (FBG) and increases insulin levels. GABA and CR are speculated to show an additive effect on insulin secretion and β-cell regeneration via GABA signaling and enhance insulin sensitivity ameliorating T2D manifestations. We have evaluated the effect of GABA and CR combination on β-cell regeneration and insulin sensitivity in High Fat Diet (HFD) and streptozotocin (STZ) induced late stage T2D mouse model. Our results show favorable changes in the measured parameters. GABA+CR group showed reduced FBG levels and improved whole-body insulin responsiveness indicated by increased insulin levels, insulin sensitivity, and glucose tolerance. The combination therapy improved the lipid profile by significantly reducing triglycerides, total cholesterol, and LDL levels and increased HDL levels. The transcript expression profile of metabolic enzymes in the liver indicates a significant decrease in gluconeogenesis and glycogenolysis. The transcript levels indicate decreased lipolysis and increased fatty acid synthesis in the adipose tissue. The transcript levels of mitochondrial biogenesis in the skeletal muscle indicate increased effect of combination therapy, thereby promoting insulin sensitivity. Also, combination therapy promoted β-cell proliferation.

In conclusion, calorie restriction in combination with GABA ameliorates T2D in the mouse model by inducing β-cell regeneration mediated by GABA and increased insulin sensitivity by CR diet.

GABA correlation to fasting AND meditation. Parasympathetic state activation leads to better insulin sensitivity and β-cell regeneration. Mindfulness is therapy too.

Muscles and Fasting

A Novel 14-Day Dietary Deprivation Regimen Preserves Protein Metabolism During Fasting and Accelerates Muscle Recovery after Refeeding Through Constantly Suppressing Myostatin

Findings Bioelectrical and biochemical results indicated significant reducing in fat mass (lipid) during fasting, while lean mass (protein) remained stable and found more accelerated recovery after refeeding. During 7~9thD CDD, we observed a significant slowing down in basal metabolism rate (BMR < 10%) with sudden alleviation in food craving (termed breaking point). We observed that, for the subjects with pathological creatine kinase (CK) baselines >100U/L, refeeding for more than 3 months remained lowered CK level. Fasting 14D also found significant suppression in myostatin, and it remained lower concentration even after 3 months' refeeding. Ultrasonic image confirmed unchanged muscle comparing with adipose during and after 14D fasting.

Interpretation Our results indicated that initial fasting (1~7D) induced catabolism in all tissues. As the fasting continues, a preserved muscle mechanism has been established with reducing in BMR, myostatin and CK which might indicate an induction of anabolism through establishing ketone body metabolism. The beneficial evidence from current regimen indicated that repeated application of 14D-CDD every 6 months may supply practical health improvement strategy in facilitating disease treatments.

Hibernation in Animals and Dry Fasting

Fat, Energy and Mammalian Survival 

Adipose tissue plays a critical role in mammalian life history strategies, serving as an organ for the storage of food and energy, as a source of heat and water and as thermal insulation. The food and energy storage roles are especially important in allowing the animals to survive food shortages and stresses associated with competition for mates, territorial defense, gestation and lactation, and to accomplish migrations. The composition, cellularity and anatomical site of adipose depots in a mammal can influence both the amount of fat stored and its availability and usefulness in any given situation. The fatty acids and complex lipids in adipose tissue, blood vessels, nerves and brain change in response to ambient temperature and the low body temperatures during hibernation. Early nutrition may influence the number of fat cells developed by a mammal, and thus affect its ability to survive adversity. Desert species develop localized depots which will not interfere with temperature regulation, while animals in cold environments use their extensive superficial fat layers as insulation.

Natural resistance to liver cold ischemia-reperfusion injury associated with the hibernation phenotype

This study observed that hibernating animals' livers were more resistant to cold ischemia-reperfusion injury (a condition that can occur during organ transplantation) than non-hibernators. Understanding the protective mechanisms could have implications for improving organ preservation in transplantation procedures.

Hibernation in ground squirrels induces state and species-specific tolerance to hypoxia and aglycemia: an in vitro study in hippocampal slices

This study observed that the brains of hibernating ground squirrels were more resistant to conditions of low oxygen (hypoxia) and low glucose (aglycemia) compared to non-hibernators. This neuroprotective benefit has potential implications for treatments of conditions like stroke and other neurodegenerative disorders.

The effect of hibernation on the growth of sarcoma in the hamster

The study found that tumor growth in European hamsters was significantly slowed during hibernation periods. This suggests potential anti-tumor mechanisms that are activated during hibernation.

Hibernation in black bears: independence of metabolic suppression from body temperature

This study, conducted on black bears, found that while the animals exhibited significantly reduced metabolic rates during hibernation, they retained high levels of muscle and bone mass despite months of inactivity. Black bears hibernate for 5 to 7 months a year and, during this time, do not eat, drink, urinate, or defecate. We measured metabolic rate and body temperature in hibernating black bears and found that they suppress metabolism to 25% of basal rates while regulating body temperature from 30° to 36°C, in multiday cycles. Heart rates were reduced from 55 to as few as 9 beats per minute, with profound sinus arrhythmia. After returning to normal body temperature and emerging from dens, bears maintained a reduced metabolic rate for up to 3 weeks. The pronounced reduction and delayed recovery of metabolic rate in hibernating bears suggest that the majority of metabolic suppression during hibernation is independent of lowered body temperature. Compare this to the common knowledge that you can expect dry fasting benefits or results to continue for 3-4 weeks post-fast. This correlates to the metabolic rate being found to return after 3 weeks for the bears upon waking.

NAD and Fasting

NMN Maintains Intestinal Homeostasis by Regulating the Gut Microbiota

The aim of this study was to determine the effects of long-term Nicotinamide mononucleotide (NMN) treatment on modulating gut microbiota diversity and composition, as well as its association with intestinal barrier function. In this study, C57BL/6J mice were fed different concentrations of NMN, and their feces were collected for detection of 16S rDNA and non-targeted metabolites to explore the effects of NMN on intestinal microbiota and metabolites. The results revealed that NMN increased the abundance of butyric acid-producing bacteria (Ruminococcae_UCG-014 and Prevotellaceae_NK3B31_group) and other probiotics (Akkermansia muciniphila), while the abundance of several harmful bacteria (Bilophila and Oscillibacter) were decreased after NMN treatment. Meanwhile, the level of bile acid-related metabolites in feces from the G1 group (0.1 mg/ml) was significantly increased compared to the control group, including cholic acid, taurodeoxycholic acid, taurocholic acid, glycocholic acid, and tauro-β-muricholic acid. In addition, long-term NMN treatment affected the permeability of the intestinal mucosa. The number of goblet cells and mucus thickness increased, as well as expression of tight junction protein. These results demonstrate that NMN reduced intestinal mucosal permeability and exerts a protective effect on the intestinal tract. This study lays the foundation for exploring NMN's utility in clinical research.

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