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Transcranial Magnetic Stimulation (TMS) for Knee pain osteoarthritis and other great things

Transcranial Direct Current Stimulation Effective for Knee OA Pain

Transcranial direct current stimulation (tDCS) can effectively alleviate osteoarthritis (OA)-related knee pain, according to results from a double-blind, randomized and sham-controlled pilot clinical study presented at the American Pain Society’s 36th Annual Scientific Meeting in Pittsburgh, Pennsylvania. Upon session completion, participants in the tDCS group showed improved analgesia compared with patients in the sham tDCS group, as indicated by reported pain ratings (on a 0 to 100 numeric scale: 18.50 ± 3.60 vs 6.45 ± 2.26; mean difference 12.05 [P =.007]).

Efficacy of Transcranial Direct Current Stimulation on Clinical Pain Severity in Older Adults with Knee Osteoarthritis Pain A Double-Blind, Randomized, Sham-Controlled Pilot Clinical S

The knee joint is the most affected one in individuals with OA, the most prevalent type of arthritis and itself a major cause of disability in individuals aged ≥45 years. Although OA pain is commonly managed pharmacologically, these treatments (eg, tapentadol, corticosteroids) are often associated with adverse effects.2,3Neuromodulation of central pain pathways therefore represents an attractive alternative for the treatment of chronic pain, including knee OA-related pain. tDCS, a noninvasive technique increasingly used for the treatment of several conditions that include chronic pain, as well as motor and psychiatric disorders, exerts its effects by depolarizing (anodal tDCS) or hyperpolarizing (cathodal tDCS) cortical neurons.4,5

The current study aimed to evaluate the efficacy of tDCS in alleviating knee OA pain. Study participants (n = 40; mean age, 59 years; ages 50 to 70 years; 53% women) were randomly assigned to receive tDCS (2 mA) or sham tDCS for 20 minutes daily over a 5-day period. tDCS electrodes were placed on the primary motor cortex of the side contralateral to the painful knee (anode) and on the supraorbital region ipsilaterally (cathode).

Story from clinical pain adviser.


Evidence-based guidelines on the therapeutic use of transcranial direct current stimulation (tDCS).


A group of European experts was commissioned by the European Chapter of the International Federation of Clinical Neurophysiology to gather knowledge about the state of the art of the therapeutic use of transcranial direct current stimulation (tDCS) from studies published up until September 2016, regarding pain, Parkinson’s disease, other movement disorders, motor stroke, poststroke aphasia, multiple sclerosis, epilepsy, consciousness disorders, Alzheimer’s disease, tinnitus, depression, schizophrenia, and craving/addiction. The evidence-based analysis included only studies based on repeated tDCS sessions with sham tDCS control procedure; 25 patients or more having received active treatment was required for Class I, while a lower number of 10-24 patients was accepted for Class II studies. Current evidence does not allow making any recommendation of Level A (definite efficacy) for any indication. Level B recommendation (probable efficacy) is proposed for: (i) anodal tDCS of the left primary motor cortex (M1) (with right orbitofrontal cathode) in fibromyalgia; (ii) anodal tDCS of the left dorsolateral prefrontal cortex (DLPFC) (with right orbitofrontal cathode) in major depressive episode without drug resistance; (iii) anodal tDCS of the right DLPFC (with left DLPFC cathode) in addiction/craving. Level C recommendation (possible efficacy) is proposed for anodal tDCS of the left M1 (or contralateral to pain side, with right orbitofrontal cathode) in chronic lower limb neuropathic pain secondary to spinal cord lesion. Conversely, Level B recommendation (probable inefficacy) is conferred on the absence of clinical effects of: (i) anodal tDCS of the left temporal cortex (with right orbitofrontal cathode) in tinnitus; (ii) anodal tDCS of the left DLPFC (with right orbitofrontal cathode) in drug-resistant major depressive episode. It remains to be clarified whether the probable or possible therapeutic effects of tDCS are clinically meaningful and how to optimally perform tDCS in a therapeutic setting. In addition, the easy management and low cost of tDCS devices allow at home use by the patient, but this might raise ethical and legal concerns with regard to potential misuse or overuse. We must be careful to avoid inappropriate applications of this technique by ensuring rigorous training of the professionals and education of the patients.

Efficacy of transcranial direct current stimulation and repetitive transcranial magnetic stimulation for treating fibromyalgia syndrome a systematic review.

 To systematically review the literature to date applying repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) for patients with fibromyalgia syndrome (FMS).


 Electronic bibliography databases screened included PubMed, Ovid MEDLINE, PsychINFO, CINAHL, and Cochrane Library. The keyword “fibromyalgia” was combined with (“transcranial” and “stimulation”) or “TMS” or “tDCS” or “transcranial magnetic stimulation” or “transcranial direct current stimulation”.


 Nine of 23 studies were included; brain stimulation sites comprised either the primary motor cortex (M1) or the dorsolateral prefrontal cortex (DLPFC). Five studies used rTMS (high-frequency-M1: 2, low-frequency-DLPFC: 2, high-frequency-DLPFC: 1), while 4 applied tDCS (anodal-M1: 1, anodal-M1/DLPFC: 3). Eight were double-blinded, randomized controlled trials. Most (80%) rTMS studies that measured pain reported significant decreases, while all (100%) tDCS studies with pain measures reported significant decreases. Greater longevity of significant pain reductions was observed for excitatory M1 rTMS/tDCS.


 Studies involving excitatory rTMS/tDCS at M1 showed analogous pain reductions as well as considerably fewer side effects compared to FDA apaproved FMS pharmaceuticals. The most commonly reported side effects were mild, including transient headaches and scalp discomforts at the stimulation site. Yearly use of rTMS/tDCS regimens appears costly ($11,740 to 14,507/year); however, analyses to apapropriately weigh these costs against clinical and quality of life benefits for patients with FMS are lacking. Consequently, rTMS/tDCS should be considered when treating patients with FMS, particularly those who are unable to find adequate symptom relief with other therapies. Further work into optimal stimulation parameters and standardized outcome measures is needed to clarify associated efficacy and effectiveness.

Transcranial Magnetic Stimulation-Mediated Analgesia is Independent of Improvements in Depression

Repetitive transcranial magnetic stimulation of the right secondary somatosensory motor cortex (S2) produces pain relief in patients with chronic neuropathic orofacial pain, an effect that was shown to be direct, and not a result of improvements in psychiatric or sleep disorder comorbidities. These findings were published in November in Medicine

The study participants had been diagnosed by a neurologist and an orofacial pain physician as follows: 7 had trigeminal neuropathic pain, 4 had atypical facial pain, and 5 had burning mouth syndrome. All patients displayed dysfunction of the trigeminal small- (and also large-, in some) fiber system, as well as a score ≥4 on the 0 to 10 numerical rating scale (NRS) for chronic daily neuropathic orofacial pain (daily average, 5.7; mean duration, 10.4 years).

Each study participant received 3 rTMS treatments (one of which was a placebo session), administered 4 weeks apart in a single-blind/within-subject manner. Stimulations (50 pulses at 90% of the resting motor threshold, every 10 s) targeted the facial area within the somatotopic representation of the primary sensorimotor cortex (S1/M1) and S2 in a random order.

Patients were assessed for psychiatric disorders based on the structured clinical interview for axis I disorders.3 Pain, mood, sleep and quality of life were assessed by study participants using the NRS to rate both pain and sleep and collected in study diaries for 4 weeks prior to and following treatment.

In addition, total hours of sleep, intensity, and interference of pain (measured using the Brief Pain Inventory),4 and sleep characteristics (assessed using the Basic Nordic Sleep Questionnaire),5 were all reported.

A more thorough assessment of sleep quality, measuring the 6 dimensions of sleep (ie, sleep disturbance , snoring, awakening with shortness of breath or headache, sleep adequacy, daytime somnolence, and quantity of sleep) was achieved through the Medical Outcomes Study (MOS) Sleep Measure, prior to and 1 month following each rTMS session.6

The authors found that neither sleep nor psychiatric disorders or medications (eg, opioids) had predictive value for rTMS treatment efficacy in study participants. The treatments had no detectable impact on either mood (assessed with the Beck Depression Inventory),7 or sleep quality.

Pain scores specific to neuropathic pain — but not to general pain — were reduced following S2 stimulation, as indicated by lower scores on the Neuropathic Pain Impact on Quality-of-Life questionnaire8 in treated vs sham-stimulated patients (P=.0031).

Six (38%) and 10 (63%) of the patients had a current or lifetime psychiatric disorder (depression or anxiety), respectively.

The authors concluded that “the present results show that the analgesic effect of rTMS given to the right S2 cortex as previously reported is most likely due to a direct action on specific top-down pain modulation networks rather than a result of an indirect action via improvement of comorbid psychiatric or sleep disturbances.”

They also added that “S2 stimulation had no effect on depressive symptoms, sleep diary measures, or the MOS sleep scale index scores, and that “comorbidities such as depression, anxiety disorders, and sleep problems did not predict the rTMS treatment outcome.”

The analgesic effect of therapeutic rTMS is not mediated or predicted by comorbid psychiatric or sleep disorders

Lindholm P, Lamusuo S, Taiminen T, et al. The analgesic effect of therapeutic rTMS is not mediated or predicted by comorbid psychiatric or sleep disorders. Medicine (Baltimore). 2016;95(44)

Lindholm P, Lamusuo S, Taiminen T, et al. Right secondary somatosensory cortex-a promising novel target for the treatment of drug-resistant neuropathic orofacial pain with repetitive transcranial magnetic stimulation. Pain. 2015;156(7):1276-1283

Right secondary somatosensory cortex-a promising novel target for the treatment of drug-resistant neuropathic orofacial pain with repetitive transcranial magnetic stimulation

Transcranial Direct Current Stimulation in Epilepsy

Results: We analyzed 9 articles with different methodologies (3 animals/6 humans) with a total of 174 stimulated individuals; 109 animals and 65 humans. In vivo and in vitro animal studies showed that direct current stimulation can successfully induce suppression of epileptiform activity without neurological injury and 4/6 (67%) clinical studies showed an effective decrease in epileptic seizures and 5/6 (83%) reduction of inter-ictal epileptiform activity. All patients tolerated tDCS well. Conclusions: tDCS trials have demonstrated preliminary safety and efficacy in animals and patients with epilepsy. Further larger studies are needed to define the best stimulation protocols and long-term follow-up.

Beck AT, Rial WY, Rickels K. Short form of depression inventory: crossvalidation. Psychol Rep. 1974;34:1184–1186




Nanoparticles and gut effects – generally recognized as safe?

Models for oral uptake of nanoparticles in consumer products

Titanium dioxide nanoparticle ingestion alters nutrient absorption in an in vitro model of the small intestine

Zhongyuan Guo, Nicole J. Martucci, Fabiola Moreno-Olivas, Elad Tako, Gretchen J. Mahler. Titanium dioxide nanoparticle ingestion alters nutrient absorption in an in vitro model of the small intestine. NanoImpact, 2017; 5: 70 DOI: 10.1016/j.impact.2017.01.002

In the study above, researchers took a meal’s worth of titanium oxide nanoparticles — 30 nanometers across — over four hours (acute exposure), or three meal’s worth over five days (chronic exposure) and determined the effect on the gut. Acute exposure caused no harm,  but chronic exposure diminished the absorptive projections on the surface of intestinal cells called microvilli. With fewer microvilli, the intestinal barrier was weakened, metabolism slowed and some nutrients — iron, zinc, and fatty acids, specifically — were more difficult to absorb. Enzyme functions were negatively affected, while inflammation signals increased. It turns out that nanoparticles are everywhere, especially in food, cosmetics, and pharmaceuticals. It can enter the digestive system through toothpastes, since Titanium dioxide is used to create abrasion needed for cleaning. The oxide is also used in some chocolate to give it a smooth texture; in donuts to provide color; and in skimmed milks for a brighter, more opaque appearance which makes the milk more palatable. Dunkin Donuts stopped using powdered sugar with titanium dioxide nanoparticles in 2015 in response to pressure from the advocacy group As You Sow.

There is emerging evidence that we have generated strategies to utilise nanoparticles for dietary and physiological benefit evolutionarily.  Thus, nanoparticulate structures are neither inherently toxic nor inherently safe: like all molecules these decisions will rest upon molecular structure, biological environment, degree of exposure and host susceptibility.

Nanoparticues act in a number of wasy internally, especially in the gut lumen, where they are exposed to mucin, proteins, pH changes, and other existing charged particles. There has been described a protein coating of nanoparticle surfaces, referred to as a ‘corona’, this phenomenon has been known for decades and will inevitably happen in the particle’s native environment. In the gastrointestinal tract it is likely that the acidic pH of the stomach, which mainly is maintained even postprandially, and the presence of gastrointestinal enzymes, will serve to denude ingested particles of their surface-adsorbed molecules but then re-adsorption of novel entities will occur in the less acidic small bowel lumen.

There are many exogenous inorganic particles are man-made particles comprising titanium dioxide or silicates/aluminosilicates. Titanium dioxide (designated E171 in Europe) is used for whitening and brightening foods, especially for confectionary, white sauces and dressings, and certain powdered foods.

Titanium dioxide (designated E171 in Europe) is used for whitening and brightening foods, especially for confectionary, white sauces and dressings, and certain powdered foods. It is also used in the pharmaceutical industry as an opacity agent. Titanium dioxide is typically found in gut tissue in the anatase polymorphic form and is a 100-200 nm diameter spherical particle that is resistant to gastrointestinal degradation. Particulate silicates and aluminosilicates (E554, E556 and E559 in Europe) are used in the food industry as anti-caking agents and to allow the flow of powders, and some are present in cheeses, sugars and powdered milks. In the UK, the major five food sources of particulate silicates are salt, drinking powders, chewing gum, instant pot savory snacks and icing sugar.Overall, intake of dietary inorganic microparticles in the UK has been estimated to be about 40 mg/person/day (35 mg for the silicates and 5 mg for titanium dioxide) which equates to a staggering daily exposure of 101214 particles/person.

How are  the partciles taken up in the gut? M-cell-uptake (transcytosis) at the surface of intestinal lymphoid aggregates is the quintessential pathway for gut particle uptake and is very well described, especially for large nanoparticles (20-100 nm) and small microparticles (100-500 nm). Hydrophobic particles appear to be much better taken up than hydrophilic particles,  and  generally, small particles are better taken up than large ones with, perhaps, an optimal size of around 50 nm diameter.

Other sources of nanoparticles (NM) relevant for oral exposure comprise mainly cosmetics (sunscreen, lipsticks, skin creams, toothpaste) and food (packaging, storage life sensors, food additives, juice clarifiers). Whereas NMs in food are intended to be ingested, nanoparticles for instance in cosmetics and ingredients in food packaging may accidently get into the gastrointestinal tract. Major materials used in these products are: silver, and metal oxides of zinc, silica, and titanium. Nanosilver (Ag) is used in food packaging. According to the Woodrow Wilson Nanotechnology Consumer Products Inventory 2011, Ag nanoparticles are the most commonly used new NM in consumer products followed by TiO2, ZnO, platinum (Pt) and silicium oxide NMs ( Although gold NMs are also used in cosmetics, food packaging, beverage and toothpaste their main applications are in the medical field.

Decrease of particle size in the nanoscale has been identified as a main parameter for the increased toxicity of different materials. Polystyrene, for instance, is a very biocompatible polymer used in cell culture. Nanoparticles, however, made from this material are cytotoxic.

Compared to other metal and metal oxide nanoparticles intake of TiO2 by food is relatively high at 5 mg TiO2/person/d .Metal and metal oxide nanoparticles can accumulate in plants  and in animals of the food chain. That is worrisome.

A number of factors effect uptake of particles by the gut. Even in healthy individuals gastrointestinal transit is by far not constant and shows considerable variation through the large intestine . These effects are known to influence oral bioavailability of conventional drugs but are even more important for the effects of NMs because NMs readily adsorb proteins. Mucus represents an efficient acellular barrier. Mucus consists of mucin proteins (highly glycosylated extracellular proteins with characteristic gel-forming properties), antiseptic proteins (lysozyme) and other proteins (lactoferrin), inorganic salts and water. The major functions are the protection and the lubrication of the underlying tissue. The saliva, which is produced by the salivary glands, mainly consists of water (up to 99.5%), inorganic salts, proteins, and mucins. The high molecular weight mucin MG1 can bind to the surface of the epithelium and build the so-called mucus layer, displaying the acellular barrier of the oral cavity The mucus of the following parts, stomach and small and large intestine, is mainly produced by intraepithelial cells, and hickness increases from proximal to distal parts of the small and large intestine . Depending on the method used for the determination, the thickness of the mucus layer shows marked variation..The characteristics facilitating the passage through human mucus are relatively well known: electrostatic repulsion from negatively charged sugar moieties favors the penetration of positively charged hydrophilic molecules; the passage of lipophilic compounds is slow. Viruses, like the Norwalk virus with a size of 38 nm and human papilloma virus with a size of 55 nm diffused in human mucus as rapidly as they do in water These findings suggest that the surface charge plays a crucial role in the transport rates of nanoparticles through a mucus layer

In addition to particle size, dose and duration of the exposure are important for the interpretation of the data. In addition to particle size, dose and duration of the exposure are important. There is  a size-dependent decrease of the uptake from 34% for 50 nm particles to 26% for 100 nm particles , and dose and duration of the exposure are also important for absorption and uptake of NM.

Changes in mucus composition induced by Ag nanoparticles (Jeong et al., 2010), polystyrene particles and diesel exhaust increased mucus permeability and permeation of small molecules by a factor of 5. Thus NM enter more quickly through disease barriers.

The adherence of polystyrene nanoparticles to inflamed colonic mucosa was much higher than to normal mucosa. Inflammation appears to increase uptake and permeation of NMs in vitro and in vivo. Inflammation caused by Yersinia pseudotuberculosis increases the uptake of 100 nm carboxyl polystyrene particles in cell monolayers and in intestinal biopsies. Other factors of absorption include pH and thickness of the mucus layer, the gastrointestinal flora and in gastrointestinal passage time (motility)

Whereas plasma membranes restrict the cellular access for metal ions like silver cations, silver nanoparticles were readily internalized and intracellular silver concentrations were much higher than for silver ions. Studies for uptake and toxicity should, therefore, include AgNO3 for silver nanoparticles (Trojan horse effect) or bulk material.. Absorption may also be altered by a changed metabolization by enterocytes. Polystyrene and silver particles have been shown to inhibit the activity of cytochrome P450 enzymes, of note

To avoid foods rich in titanium oxide nanoparticles you should avoid processed foods, and especially candy. This information may make one question if these NM have any impact on the surge of colitis seen ion the general poplulation? How about autoimmune diseases? How about general inflammation, for if NM damage the intestinal barrier, inflammation results and it’s attendant consequences.

MIND diet and complex nutritional interactions


Hybrid ‘MIND’ Diet Keeps Aging Brain Sharp

MIND diet slows cognitive decline with aging.

Physical Activity Recommendations for the Aging Brain A Clinician-Patient Guide

Is the Mediterranean diet a feasible approach to preserving cognitive function and reducing risk of dementia

Detoxification reactions Relevance to aging

Dietary patterns, cognitive decline, and dementia a systematic review.

Are Anxiety Disorders Associated with Accelerated Aging A Focus on Neuroprogression.

Mediterranean Diet, Cognitive Function, and Dementia A Systematic Review

Highlights From the Institute for Functional Medicine’s 2014 Annual Conference Functional Perspectives on Food and NutritionThe Ultimate Upstream Medicine.

“MIND” is an acronym for Mediterranean-DASH Diet Intervention for Neurodegenerative Delay. Both the Mediterranean and DASH diets have been found to reduce the risk for hypertension, myocardial infarction, and stroke.

What Are the Components to the MIND Diet

MIND diet associated with reduced incidence of Alzheimer’s disease

The MIND diet has 15 dietary components, including 10 “brain-healthy” food groups and five unhealthy groups (ie, red meat, butter and stick margarine, cheese, pastries and sweets, and fried or fast food). To stick to the MIND diet, a person has to limit intake of the designated unhealthy foods, especially butter (<1 tablespoon/day), sweets and pastries, whole fat cheese, and fried or fast food (<1 serving a week for any of the three). As for the brain-healthy foods, a person would need to eat at least three servings of whole grains, a green leafy vegetable, and one other vegetable each day, along with having a glass of wine. They would also need to snack most days on nuts, have beans every other day or so, and eat poultry and berries at least two times a week (berries are the only fruits allowed in the MIND diet) and fish at least once a week. The overall rate of change in cognitive score was a decline of 0.8 standardized score units per year. In mixed models adjusted for a variety of relevant factors, including age, sex, education, total energy intake, APOE4 carrier status, and participation in cognitive activities, the MIND diet score was “positively and statistically significantly” associated with slower decline in global cognitive score (β = 0.0092; P < .0001) and with five cognitive domains, especially episodic memory, semantic memory, and perceptual speed, the researchers report. If a person is eating in a manner that is heart healthy, that’s probably also going to be brain healthy, because the brain does use so much of the nutrients and the oxygen that are carried in the vascular system, and as you age, if your brain isn’t getting enough nutrients and oxygen, it is going to be less likely to be able to deal with other factors that cause Alzheimer’s disease or other dementias. 

Dietary intakes of berries and flavonoids in relation to cognitive decline  Results: Greater intakes of blueberries and strawberries were associated with slower rates of cognitive decline (eg, for a global score averaging all 6 cognitive tests, for blueberries: p-trend ¼ 0.014 and mean difference ¼ 0.04, 95% confidence interval [CI] ¼ 0.01–0.07, comparing extreme categories of intake; for strawberries: p-trend ¼ 0.022 and mean difference ¼ 0.03, 95% CI ¼ 0.00–0.06, comparing extreme categories of intake), after adjusting for multiple potential confounders. These effect estimates were equivalent to those we found for approximately 1.5 to 2.5 years of age in our cohort, indicating that berry intake appears to delay cognitive aging by up to 2.5 years. Additionally, in further supporting evidence, greater intakes of anthocyanidins and total flavonoids were associated with slower rates of cognitive decline (p-trends ¼ 0.015 and 0.053, respectively, for the global score). Interpretation: Higher intake of flavonoids, particularly from berries, appears to reduce rates of cognitive decline in older adults.

Diet and Cognitive Decline Untangling the Evidence

When it comes to single or multiple nutrients, the evidence has also exploded. For example, omega-3 fatty acids or E vitamins, curcumin, vitamin D, and caffeinated foods: These are all different dietary components that may or may not play a role in development of Alzheimer disease. Dr Martha Clare Morris and her colleagues from Rush University presented a great paper that studied very specific brain-healthy eating patterns, which she calls the MIND diet, with the results suggesting a reduction in the likelihood of developing cognitive impairment significantly over several years.  omega-3 fatty acids: First of all, not all omega-3’s are created equal. DHA and EPA have the most evidence for reducing a person’s risk of developing cognitive decline. The key here is that certain people with different genes may respond preferentially; people with an ApoE4 gene may respond favorably while people without that gene may respond less. When it comes to Alzheimer’s treatment, those omega-3’s didn’t pan out in terms of randomized studies, but omega-3’s used for Alzheimer’s prevention or risk reduction are something we want to think about. Also, when it comes to personalized medicine based on genes, we can focus on Alzheimer disease in a new area called clinical precision medicine, where we look not only at genetics, but also at people’s individual biologies, nutritional patterns, and lifestyle patterns, and then give a clinically precise approach for treatment or prevention. For example, if a person has high homocysteine levels, then B complex vitamins—folic acid, B12, and B6—in randomized studies have been shown to slow overall brain atrophy as well as increase memory function. The key take-home point here is that B complex therapy only works in patients who have high homocysteine levels and those who have an adequate level of omega-3’s in the blood. When it comes to blueberries, you’ve heard about flavonols. Dark cocoa powder may be effective for boosting memory. You can’t just eat one blueberry and think you’re going to prevent or cure Alzheimer disease—it doesn’t work that way. But in the Nurses’ Health Study,[3] a half a cup of blueberries two to three times a week was shown to delay the onset of cognitive decline.

Cocoa flavanol consumption improves cognitive function, blood pressure control, and metabolic profile in elderly subjects the Cocoa, Cognition, and Aging (CoCoA) Study : This dietary intervention study provides evidence that regular CF consumption can reduce some measures of age-related cognitive dysfunction, possibly through an improvement in insulin sensitivity. These data suggest that the habitual intake of flavanols can support healthy cognitive function with age. Abstract—Flavanol consumption is favorably associated with cognitive function. We tested the hypothesis that dietary flavanols might improve cognitive function in subjects with mild cognitive impairment. We conducted a double-blind, parallel arm study in 90 elderly individuals with mild cognitive impairment randomized to consume once daily for 8 weeks a drink containing 990 mg (high flavanols), 520 mg (intermediate flavanols), or 45 mg (low flavanols) of cocoa flavanols per day. Cognitive function was assessed by Mini Mental State Examination, Trail Making Test A and B, and verbal fluency test. At the end of the follow-up period, Mini Mental State Examination was similar in the 3 treatment groups (P0.13). The time required to complete Trail Making Test A and Trail Making Test B was significantly (P0.05) lower in subjects assigned to high flavanols (38.1010.94 and 104.1028.73 seconds, respectively) and intermediate flavanols (40.2011.35 and 115.9728.35 seconds, respectively) in comparison with those assigned to low flavanols (52.6017.97 and 139.2343.02 seconds, respectively). Similarly, verbal fluency test score was significantly (P0.05) better in subjects assigned to high flavanols in comparison with those assigned to low flavanols (27.506.75 versus 22.308.09 words per 60 seconds). Insulin resistance, blood pressure, and lipid peroxidation also decreased among subjects in the high-flavanol and intermediate-flavanol groups. Changes of insulin resistance explained 40% of composite z score variability through the study period (partial r2 0.4013; P0.0001). To the best of our knowledge, this is the first dietary intervention study demonstrating that the regular consumption of cocoa flavanols might be effective in improving cognitive function in elderly subjects with mild cognitive impairment. This effect appears mediated in part by an improvement in insulin sensitivity. 

Benefits in Cognitive Function, Blood Pressure, and Insulin Resistance Through Cocoa Flavanol Consumption in Elderly Subjects With Mild Cognitive Impairment

9 Brain Boosting Benefits of Dark Chocolate


The effect of flavanol-rich cocoa on cerebral perfusion in healthy older adults during conscious resting state

Results Significant increases in regional perfusion across the brain were observed following consumption of the high flavanol drink relative to the low flavanol drink, particularly in the anterior cingulate cortex and the central opercular cortex of the parietal lobe.

The prevention and treatment of cognitive decline and dementia_ An overview of recent research on experimental treatments

Diet and Alzheimer’s disease risk factors or prevention the current evidence

Polyphenol Stilbenes Molecular Mechanisms of Defence against Oxidative Stress and Aging-Related Diseases.

Phytochemical Compounds and Antioxidant Capacity of Tucum-Do-Cerrado (Bactris setosa Mart), Brazil’s Native Fruit.

Polyphenols multipotent therapeutic agents in neurodegenerative diseases.

Pinosylvin-mediated protection against oxidative stress in human retinal pigment epithelial cells.

Mechanisms of Neuroprotection by Quercetin Counteracting Oxidative Stress and More.

Antioxidants inhibit neuronal toxicity in Parkinson’s disease-linked LRRK2.

New formulations for preventing Alzheimer’s – functional medical foods

A multi-ingredient dietary supplement abolishes large-scale brain cell loss, improves sensory function, and prevents neuronal atrophy in aging mice

Transgenic growth hormone mice (TGM) are a recognized model of accelerated aging with characteristics including chronic oxidative stress, reduced longevity, mitochondrial dysfunction, insulin resistance, muscle wasting, and elevated inflammatory processes. Growth hormone/IGF-1 activate the Target of Rapamycin known to promote aging. TGM particularly express severe cognitive decline. We previously reported that a multi-ingredient dietary supplement (MDS) designed to offset five mechanisms associated with aging extended longevity, ameliorated cognitive deterioration and significantly reduced age-related physical deterioration in both normal mice and TGM. Here we report that TGM lose more than 50% of cells in midbrain regions, including the cerebellum and olfactory bulb. This is comparable to severe Alzheimer’s disease and likely explains their striking agerelated cognitive impairment. We also demonstrate that the MDS completely abrogates this severe brain cell loss, reverses cognitive decline and augments sensory and motor function in aged mice. Additionally, histological examination of retinal structure revealed markers consistent with higher numbers of photoreceptor cells in aging and supplemented mice. We know of no other treatment with such efficacy, highlighting the potential for prevention or amelioration of human neuropathologies that are similarly associated with oxidative stress, inflammation and cellular dysfunction. Environ. Mol. Mutagen. 57:382–404, 2016.

A dietary supplement containing ingredients commonly found in health food stores appears to prevent the decline in brain structure and function typically seen in Alzheimer’s disease, the results of an animal study indicate.  Dietary Supplement May Prevent Cognitive Decline    In a mouse model of accelerated aging and severe cognitive decline, a combination of vitamins and minerals, as well as nutraceuticals, such as beta carotene, bioflavonoids, cod liver oil, flax seed, garlic, and green tea extract, not only maintained brain cell numbers and mass and cognitive function but also appeared to prevent deterioration of sight and smell. Mechanisms of degenration , which include oxidative stress, inflammation, and mitochondrial dysfunction, “happen in a multitude of species as they get older” and are not “something that is specifically a human phenomenon that has been attempted to be recreated in a mouse model.

Effects of treatment with a multi-ingredient dietary supplement designed to ameliorate key mechanisms of aging showed treatment was associated with reduced anxiety-like behaviors, augmented discrimination of environmental context, improved motor balance, and improved visual and olfactory acuity. This was correlated with positive morphological changes and higher neuronal populations in the cerebellum and olfactory bulb, increased overall brain cell numbers and improved brain function. Intact olfaction is strongly indicative of suppression of neuronal degeneration. Retinal atrophy (associated with AMD) was also diminished in supplemented mice. Given that MDS treatment has been shown to signifi-cantly reduce oxidative damage, boost mitochondrial function [Lemon et al 2008a,b; Aksenov et al., 2010; Aksenov et al., 2013] and alleviate symptoms of inflammation [Lemon et al., 2005], suggests that neuronal protection and sensory function are likely attributed to diminishing oxidative/inflammatory stress and improved energy balance. The extent of functional benefits attained by our MDS here and in earlier studies [Lemon et al., 2003, 2005, 2008a,b; Aksenov et al., 2010, 2013; Long et al., 2012; Hutton et al., 2015’ strongly suggests that aging animals retain the capacity to support youthful phenotypes and that powerful impacts can be achieved through multi-ingredient dietary supplementation that addresses the multifactorial nature of aging organisms.

A Complex Dietary Supplement Extends Longevity of Mice

A Dietary Supplement Abolishes Age-Related Cognitive Decline in Transgenic Mice Expressing Elevated Free Radical Processes

Finding Ponce de Leon’s Pill Challenges in Screening for Anti-Aging Molecules

Lifespan and healthspan extension by resveratrol

Screening SIRT1 Activators from Medicinal Plants as Bioactive Compounds against Oxidative Damage in Mitochondrial Function.

Table 1. Formulation of a Dietary Supplement Designed to Reduce Oxidative Stress and Inflammation, Maintain Membrane and Mitochondrial Integrity, and Enhance Insulin Sensitivity Supplement Dosage Vitamin B1b 0.72 mg/day Vitamin B3b 0.72 mg/day Vitamin B6b 0.72 mg/day Vitamin B12b 0.72 mcg/day Vitamin Cb 3.6 mg/day Vitamin Db 2.5 IU/day Vitamin Eb 1.44 IU/day Acetyl L-carnitinec 14.4 mg/day Alpha-lipoic acide 0.72 mg/day ASAd 2.5 mg/day Beta caroteneb 50.0 IU/day Bioflavinoidsh 4.32 mg/day Chromium picolinatei 1.44 mcg/day Cod liver oilb 5.04 IU/day CoEnzyme Q10h 0.44 mg/day DHEAg 0.15 mg/day Flax seed oilh 21.6 mg/day Folic acidb 0.01 mg/day Garlicb 21.6 mcg/day Gingerh 7.2 mg/day Gingko bilobah 1.44 mg/day Ginseng (Canadian)h 8.64 mg/day Green tea extractsf 7.2 mg/day L-Glutathionea 0.36 mg/day Magnesiumb 0.72 mg/day Melatoning 0.01 mg/day N-Acetyl cysteinee 7.2 mg/day Potassiumb 0.36 mg/day Rutinh 0.72 mg/day Seleniumh 1.08 mcg/day Zinc (chelated)b 0.14 mg/day

Vitamin brands are as follows: a ¼ Cell Life; b ¼ Jamieson vitamins; c ¼ Jarrow Formulas; d ¼ Lifebrand; e ¼ Natural Factors; f ¼ Naka; g ¼ Promatrix; h ¼ Swiss vitamins; i ¼ Vitamin Power Inc

That is typically because our cells are working in such a complex way that we have many mechanisms that are occurring simultaneously, and when something’s going wrong, it’s usually knocking everything out of balance. When the level of one particular component is increased in the cells, “you tend to also knock everything out of whack.

Previous research by the team showed that the supplement extended longevity and reduced cognitive and age-related physical deterioration in both normal mice and transgenic growth hormone mice (TGM). TGM are characterized by accelerated aging accompanied by severe cognitive decline, as well long-term oxidative stress, insulin resistance, and other traits.
For the current study, the team mated heterozygous TGM and normal mice to create equal numbers of TGM and normal mice with a similar genetic background. The mice were then randomly assigned at weaning either to receive a liquid form of the supplement every day, with the doses of the ingredients adjusted to correspond to the amounts recommended for humans, or to be left untreated.

The mice then underwent a series of somatosensory tests to determine the severity of age-related losses in motor coordination and overall mobility. Their brains were examined for histologic changes, and the degree of apoptosis and changes in cell counts were assessed. Single-photon emission computed tomography and positron-emission tomography scanning was also performed.

The team found that compared with normal mice, untreated TGM displayed brain cell losses, deterioration of sensory function, and reductions in cerebral metabolic rate and blood perfusion that were equivalent to those seen in patients with Alzheimer’s disease.

Specifically, the mice had greater than a 50% loss at a cellular level, a 36% reduction in brain mass, and at least twofold reductions in brain metabolism and blood flow at 12 months. Furthermore, in the untreated TGM, motor and cognitive functions were severely compromised. 

Although the supplement did not have significant effects on brain cell numbers, brain weight, or brain metabolism or perfusion in normal mice, it had striking effects in TGM.

With the supplement, brain mass and brain cell density were maintained at levels seen in young mice. Brain metabolic activity was comparable to that in control mice, with no significant difference between the groups. Moreover, the supplement was associated with a twofold increase in brain perfusion in TGM.


The results also showed that the supplement restored cognitive function in TGM and led to significant improvements in motor coordination. It also appeared to reduce anxiety, allowing TGM to explore “unsafe/novel” environments.

The team found that the supplement appeared to offset deterioration of visual acuity in TGM. It was associated with increases in the thickness of the retinal outer nuclear layer and outer segment of 26% and 29%, respectively, in TGM compared with untreated mice.

TGM that received the supplement also showed improvements in olfactory sensitivity and greater numbers of mitral cells in the olfactory bulb in comparison with untreated mice. Inasmuch as olfactory loss is associated with an increased risk of developing severe neurodegenerative conditions, the researchers say these findings suggest that the supplement may be offsetting neurodegeneration throughout the brain.

Above from Medscape:

Vitamin B12 May Slow Brain Aging

total brain volume losses were lower in individuals with higher baseline vitamin B12 levels, whereas the opposite was true of those with increased homocysteine levels. Vitamin B12 and tHcy [total homocysteine] might be independent predictors of markers of brain aging in elderly individuals without dementia. Venous blood samples were collected at baseline, from which circulating levels of vitamin B12, red blood cell folate, and sulfur amino acids were determined. These were correlated with changes in brain tissue volumes and total white matter hyperintensity (WMH) over 6 years

Between baseline and the 6-year follow-up, the mean total brain tissue (TBT) volume decreased from 74.3% to 71.6% of the total cranial volume (P < .001), whereas the mean WMH volume increased from 0.0004% to 0.0007% (P < .001).

Multiadjusted linear mixed model analysis revealed that increased baseline levels of vitamin B12 and holotranscobalamin (the biologically active fraction of B12) were associated with a decreased rate of TBT volume loss, at respective beta values of 0.048 (P < .001) and 0.040 (P = .002) for each standard deviation increase. Furthermore, the researchers found that each standard deviation increase in total homocysteine levels was linked to more rapid rates of TBT volume loss, at a beta value of -0.035 (P = .02). Increases in total homocysteine levels were also associated with increases in the progression of WMH in individuals with a systolic blood pressure >140 mmHg, at 0.000019 per standard deviation increase (P = .047).

Association of Vitamin B12, Folate, and Sulfur Amino Acids With Brain Magnetic Resonance Imaging Measures in Older Adults

Results  In the multi-adjusted linear mixed models, among 501 participants (300 women [59.9%]; mean [SD] age, 70.9 [9.1] years), higher baseline vitamin B12 and holotranscobalamin levels were associated with a decreased rate of total brain volume loss during the study period: for each increase of 1 SD, β (SE) was 0.048 (0.013) for vitamin B12 (P < .001) and 0.040 (0.013) for holotranscobalamin (P = .002). Increased total homocysteine levels were associated with faster rates of total brain volume loss in the whole sample (β [SE] per 1-SD increase, –0.035 [0.015]; P = .02) and with the progression of white matter hyperintensity among participants with systolic blood pressure greater than 140 mm Hg (β [SE] per 1-SD increase, 0.000019 [0.00001]; P = .047). No longitudinal associations were found for red blood cell folate and other sulfur amino acids.

Conclusions and Relevance  This study suggests that both vitamin B12 and total homocysteine concentrations may be related to accelerated aging of the brain. Randomized clinical trials are needed to determine the importance of vitamin B12 supplementation on slowing brain aging in older adults.

Homocysteine-Lowering by B Vitamins Slows the Rate of Accelerated Brain Atrophy in Mild Cognitive Impairment A Randomized Controlled Trial

Methods and Findings

Single-center, randomized, double-blind controlled trial of high-dose folic acid, vitamins B6 and B12 in 271 individuals (of 646 screened) over 70 y old with mild cognitive impairment. A subset (187) volunteered to have cranial MRI scans at the start and finish of the study. Participants were randomly assigned to two groups of equal size, one treated with folic acid (0.8 mg/d), vitamin B12 (0.5 mg/d) and vitamin B6 (20 mg/d), the other with placebo; treatment was for 24 months. The main outcome measure was the change in the rate of atrophy of the whole brain assessed by serial volumetric MRI scans.


A total of 168 participants (85 in active treatment group; 83 receiving placebo) completed the MRI section of the trial. The mean rate of brain atrophy per year was 0.76% [95% CI, 0.63–0.90] in the active treatment group and 1.08% [0.94–1.22] in the placebo group (P = 0.001). The treatment response was related to baseline homocysteine levels: the rate of atrophy in participants with homocysteine >13 µmol/L was 53% lower in the active treatment group (P = 0.001). A greater rate of atrophy was associated with a lower final cognitive test scores. There was no difference in serious adverse events according to treatment category.

Conclusions and Significance

The accelerated rate of brain atrophy in elderly with mild cognitive impairment can be slowed by treatment with homocysteine-lowering B vitamins. Sixteen percent of those over 70 y old have mild cognitive impairment and half of these develop Alzheimer’s disease. Since accelerated brain atrophy is a characteristic of subjects with mild cognitive impairment who convert to Alzheimer’s disease, trials are needed to see if the same treatment will delay the development of Alzheimer’s disease.

the single-center, randomized VITACOG study, in which 271 individuals older than 70 years who had mild cognitive impairment received supplementation with high-dose folic acid and vitamins B6 and B12. They lost less brain compared to people who had normal homocysteine and normal vitamin levels, meaning that those with high levels of homocysteine or with clinical or biochemical vitamin deficiency can benefit from supplementation.


Medical Food Linked to Memory Improvement in Mild Alzheimer’s

Presented here at the Alzheimer’s Association International Conference (AAIC) 2012, results from an open-label extension (OLE) trial of a medical nutrition product (Souvenaid, Nutricia/Danone) showed that memory performance continued to improve in drug-naïve patients with mild AD for up to 48 weeks.

Efficacy of Souvenaid in Mild Alzheimer’s

Efficacy of Souvenaid in Mild Alzheimer’s Disease: Results from a Randomized, Controlled Trial
Abstract: Souvenaid aims to improve synapse formation and function. An earlier study in patients with Alzheimer’s disease (AD) showed that Souvenaid increased memory performance after 12 weeks in drug-naïve patients with mild AD. The Souvenir II study was a 24-week, randomized, controlled, double-blind, parallel-group, multi-country trial to confirm and extend previous findings in drug-naïve patients with mild AD. Patients were randomized 1:1 to receive Souvenaid or an iso-caloric control product once daily for 24 weeks. The primary outcome was the memory function domain Z-score of the Neuropsychological Test Battery (NTB) over 24 weeks. Electroencephalography (EEG) measures served as secondary outcomes as marker for synaptic connectivity. Assessments were done at baseline, 12, and 24 weeks. The NTB memory domain Z-score was significantly increased in the active versus the control group over the 24-week intervention period (p=0.023; Cohen’s d=0.21; 95% confidence interval [-0.06]–[0.49]). A trend for an effect was observed on the NTB total composite z- score (p=0·053). EEG measures of functional connectivity in the delta band were significantly different between study groups during 24 weeks in favor of the active group. Compliance was very high (96.6% [control] and 97.1% [active]).  No difference between study groups in the occurrence of (serious) adverse events. This study demonstrates that Souvenaid is well tolerated and improves memory performance in drug-naïve patients with mild AD. EEG outcomes suggest that Souvenaid has an effect on brain functional connectivity, supporting the underlying hypothesis of changed synaptic activity.

Efficacy of a medical food in mild Alzheimer’s disease: A randomized, controlled trial     Below:



To investigate the effect of a medical food on cognitive function in people with mild Alzheimer’s disease (AD).


A total of 225 drug-naïve AD patients participated in this randomized, double-blind controlled trial. Patients were randomized to active product, Souvenaid, or a control drink, taken once-daily for 12 weeks. Primary outcome measures were the delayed verbal recall task of the Wechsler Memory Scale–revised, and the 13-item modified Alzheimer’s Disease Assessment Scale–cognitive subscale at week 12.


At 12 weeks, significant improvement in the delayed verbal recall task was noted in the active group compared with control (P = .021). Modified Alzheimer’s Disease Assessment Scale–cognitive subscale and other outcome scores (e.g., Clinician Interview Based Impression of Change plus Caregiver Input, 12-item Neuropsychiatric Inventory, Alzheimer’s disease Co-operative Study–Activities of Daily Living, Quality of Life in Alzheimer’s Disease) were unchanged. The control group neither deteriorated nor improved. Compliance was excellent (95%) and the product was well tolerated.


Supplementation with a medical food including phosphatide precursors and cofactors for 12 weeks improved memory (delayed verbal recall) in mild AD patients. This proof-of-concept study justifies further clinical trials. – ALZHEIMERS mixture Link

Synapse loss, he said, is an early event in the AD process. By providing the nutritional precursors and cofactors for synapse formation, researchers hope to support the formation and function of synapses.

The once-a-day drink contains a patented nutrient combination with the following ingredients:

  • Eicospentaenoic acid, 300 mg
  • Docosahexaenoic acid, 1200 mg
  • Phospholipids 106 mg
  • Choline, 400 mg
  • Uridine monophosphate, 625 mg
  • Vitamin E (alpha-tocopherol equivalents), 40 mg
  • Selenium, 60 µg
  • Vitamin B12, 3 µg
  • Vitamin B6, 1 mg
  • Folic acid, 400 µg

The current findings also showed there was a statistically significant beneficial effect on memory in favor of Souvenaid at 6 months. Of the 238 patients who completed this trial, 198 participants entered the OLE study. Of these participants, 181 completed it. The results revealed that at 48 weeks, the product was well tolerated with no serious adverse events. In addition, the compliance rate was more than 90% The OLE results also revealed that memory performance as measured by the neuropsychological test battery (NTB) continued to improve significantly in study participants who received Souvenaid for the full 48 weeks (P = .025). In addition, in the group that received placebo for the first 24 weeks, there was a significant improvement in NTB memory scores during the OLE following conversion to the active treatment (P = .009).




Gintonin, a Ginseng-Derived Lyophosphatidic acid recepto ligand attenuates alzheimers

Medical Error – everyone makes mistakes – patients and doctors

The trouble with the world
is that the stupid are cocksure
and the intelligent are full of doubt.
— Bertrand Russell

Health Affairs Website Link

Global Trigger Tool Shows That Adverse Events In Hospitals May Be Ten Times Greater Than Previously Measured

To Err is Human – IOM 1999

A comparison of hospital adverse events identified by three widely used detection methods

Medical Error and death

Medical error and death medscape article

Medical error—the third leading cause of death in the US

Patient Safety in American hospitals 2004


Makary and Daniel noted that a “medical error” may or may not cause harm to the patient and defined an error as:

  • An unintended act (either of commission or omission);
  • An act that does not achieve its intended outcome;
  • The failure of a planned action to be completed (an error of execution);
  • The use of a wrong plan to achieve an aim (an error of planning); or
  • Deviation from the process of care.


Cognitive-proximity biases; the Kübler-Ross sequence of denial and anger; the psychological need to assign blame; the risks associated with procedural management of cancer or cardiovascular disease in an unstable, aging population; and retrospective cause-and-effect attributions are all driving factors in random catastrophic lethal events being attributed inappropriately to healthcare provider-caused errors.
Preventable systematic lethal or egregious human errors do occur, but overall they are relatively small in number compared with random, unpreventable events. Oversight efforts to prevent these errors (eg, electronic health records) can have the opposite unintended consequence of increased random events, because quality provider-patient clinical ‘face time’ is reduced.

Other clinicians from the “error happens” camp believe that systems, not humans, are largely to blame for errors. A registered nurse explained. “System errors, not people intent on making mistakes, are the main culprit. Tort reform is much needed because many family members who feel the pain of loss are eager to punish someone for a loved one’s death.”

Errors are not the fault of physicians but of systems. Human disease and top causes of death have changed from acute infections to chronic problems, but the mindset that drugs and interventions that worked so well in the past are also the solution in today’s world is wrong. It is a sign that medicine needs to change with the times. We should be putting more emphasis on preventive medicine, holistic approaches, and physiological nutrition, because the drugs and interventions are doing nothing to stop the top killers.

There may no doubt that many deaths are due to clinician, nursing, and pharmacy error. Yet nowhere is it accounted for that the population as a whole is horribly sick from their own devices

Death certificates depend on International Classification of Diseases (ICD) codes for cause of death, so causes such as human and system errors are not recorded on them.

Unskilled and unaware of it: How difficulties in recognizing one’s own incompetence lead to inflated self-assessments.

People tend to hold overly favorable views of their abilities in many social and intellectual domains. The authors suggest that this overestimation occurs, in part, because people who are unskilled in these domains suffer a dual burden: Not only do these people reach erroneous conclusions and make unfortunate choices, but their incompetence robs them of the metacognitive ability to realize it. Across 4 studies, the authors found that participants scoring in the bottom quartile on tests of humor, grammar, and logic grossly overestimated their test performance and ability. Although their test scores put them in the 12th percentile, they estimated themselves to be in the 62nd. Several analyses linked this miscalibration to deficits in metacognitive skill, or the capacity to distinguish accuracy from error. Paradoxically, improving the skills of the participants, and thus increasing their metacognitive competence, helped them recognize the limitations of their abilities.

Has it ever seemed to you that less competent people rate their competence higher than it actually is, while more competent people humbly rate theirs lower?

It’s not just your imagination. This is a genuine cognitive bias called the Dunning-Kruger Effect.

The Dunning-Kruger experiments behind the research focused on cognitive tasks (logic, grammar, and evaluating humor), but similar disparities exist in other areas. In self-assessment of IQ, below-average people overestimated their score and those above average underestimated.

Studies of healthy and unhealthy behaviors are handicapped when they rely on self-reporting because test subjects tend to improve their evaluation. In self-evaluations of driving ability, job performance, and even immunity to bias, we tend to polish our image.

This is called the Lake Wobegone Effect, named after the town where “all the children are above average.”

Notice that there are two different categories of error:

(1) the error where there is a preferred answer and most people are biased toward giving that answer (“How much snack food do you eat?” or “How popular would you say you are?” or “How good a driver are you?”), and

(2) the error where bias changes depending on actual competence, with the less and more competent groups rating themselves too high and too low, respectively.

Let’s look at the second category, where the two extremes make opposite errors. The Dunning-Kruger research hypothesizes that the competent overestimate others’ skill levels. But the error is more complicated for the incompetent—they overestimate their own skill level and they lack the metacognition to realize their error. In other words, they were too incompetent to recognize their own incompetence. Improving their metacognitive skills drove down their self-assessment scores as they became better evaluators of their own limitations.

Medical Errors Are No. 3 Cause Of U.S Deaths, Researchers Say

According to the CDC, in 2013, 611,105 people died of heart disease, 584,881 died of cancer, and 149,205 died of chronic respiratory disease—the top three causes of death in the U.S. The newly calculated figure for medical errors puts this cause of death behind cancer but ahead of respiratory disease. Analyzing medical death rate data over an eight-year period, Johns Hopkins patient safety experts have calculated that more than 250,000 deaths per year are due to medical error in the U.S. Their figure, published May 3 in The BMJ, surpasses the U.S. Centers for Disease Control and Prevention’s third leading cause of death—respiratory disease, which kills close to 150,000 people per year.  Most errors represent systemic problems, including poorly coordinated care, fragmented insurance networks, the absence or underuse of safety nets, and other protocols, in addition to unwarranted variation in physician practice patterns that lack accountability.

The authors also suggest that hospitals carry out a rapid and efficient independent investigation into deaths to determine whether error played a role. A root cause analysis approach would help while offering the protection of anonymity. It’s public pressure that brings about change. Hospitals have no incentive to publicize errors; neither do doctors or any other provider. However, such a major step as adding error information to death certificates is unlikely if not accompanied by tort reform. Medical Error Is Third Leading Cause of Death in US

Medical Error in Public Eye at Geriatrics Meeting  Medical Error in Public Eye at Geriatrics Meeting

To Err Is Human, for a Pathologist to Apologize Is Uncommon

Better Handoffs Cut Medical Errors 30% in Multicenter Trial

Changes in Medical Errors after Implementation of a Handoff Program NEJM

Who Believes That Medical Error Is the Third Leading Cause of Hospital Deaths


Medical error in the US Excerpt See article below:

Analyzing medical death rate data over an eight-year period, Johns Hopkins patient safety experts have calculated that more than 250,000 deaths per year are due to medical error in the U.S. Their figure, published May 3 in The BMJ, surpasses the U.S. Centers for Disease Control and Prevention’s third leading cause of death—respiratory disease, which kills close to 150,000 people per year.

The Johns Hopkins team says the CDC’s way of collecting national health statistics fails to classify medical errors separately on the death certificate. The researchers are advocating for updated criteria for classifying deaths on death certificates.

“Incidence rates for deaths directly attributable to medical care gone awry haven’t been recognized in any standardized method for collecting national statistics,” says Martin Makary, professor of surgery at the Johns Hopkins University School of Medicine and an authority on health reform. “The medical coding system was designed to maximize billing for physician services, not to collect national health statistics, as it is currently being used.”

In 1949, Makary says, the U.S. adopted an international form that used International Classification of Diseases billing codes to tally causes of death.

“At that time, it was under-recognized that diagnostic errors, medical mistakes, and the absence of safety nets could result in someone’s death,” says Makary, “and because of that, medical errors were unintentionally excluded from national health statistics.”

In their study, the researchers examined four separate studies that analyzed medical death rate data from 2000 to 2008. Then, using hospital admission rates from 2013, they extrapolated that based on a total of 35,416,020 hospitalizations, 251,454 deaths stemmed from a medical error, which the researchers say now translates to 9.5 percent of all deaths each year in the U.S.

According to the CDC, in 2013, 611,105 people died of heart disease, 584,881 died of cancer, and 149,205 died of chronic respiratory disease—the top three causes of death in the U.S. The newly calculated figure for medical errors puts this cause of death behind cancer but ahead of respiratory disease.

“Top-ranked causes of death as reported by the CDC inform our country’s research funding and public health priorities,” Makary says. “Right now, cancer and heart disease get a ton of attention, but since medical errors don’t appear on the list, the problem doesn’t get the funding and attention it deserves.”

The researchers caution that most medical errors aren’t due to inherently bad doctors, and that reporting these errors shouldn’t be addressed by punishment or legal action. Rather, they say, most errors represent systemic problems, including poorly coordinated care, fragmented insurance networks, the absence or underuse of safety nets, and other protocols, in addition to unwarranted variation in physician practice patterns that lack accountability.

“Unwarranted variation is endemic in health care,” Makary says. “Developing consensus protocols that streamline the delivery of medicine and reduce variability can improve quality and lower costs in health care. More research on preventing medical errors from occurring is needed to address the problem.”

Whole grains increase healthfulness – new studies show

Whole grain intake is related to a clear dose-dependent reduction in the risk for coronary heart disease, stroke, cardiovascular disease, total cancer deaths, and all-cause mortality, the authors of a new meta-analysis report. They observed a similar relationship between whole grains and the risk for respiratory disease, diabetes, infectious disease, and deaths not related to cardiovascular disease or cancer.

Whole grain consumption and risk of cardiovascular disease, cancer, and all cause and cause specific mortality: systematic review and dose-response meta-analysis of prospective studies

Conclusions This meta-analysis provides further evidence that whole grain intake is associated with a reduced risk of coronary heart disease, cardiovascular disease, and total cancer, and mortality from all causes, respiratory diseases, infectious diseases, diabetes, and all non-cardiovascular, non-cancer causes. These findings support dietary guidelines that recommend increased intake of whole grain to reduce the risk of chronic diseases and premature mortality.

Results 45 studies (64 publications) were included. The summary relative risks per 90 g/day increase in whole grain intake (90 g is equivalent to three servings—for example, two slices of bread and one bowl of cereal or one and a half pieces of pita bread made from whole grains) was 0.81 (95% confidence interval 0.75 to 0.87; I2=9%, n=7 studies) for coronary heart disease, 0.88 (0.75 to 1.03; I2=56%, n=6) for stroke, and 0.78 (0.73 to 0.85; I2=40%, n=10) for cardiovascular disease, with similar results when studies were stratified by whether the outcome was incidence or mortality. The relative risks for morality were 0.85 (0.80 to 0.91; I2=37%, n=6) for total cancer, 0.83 (0.77 to 0.90; I2=83%, n=11) for all causes, 0.78 (0.70 to 0.87; I2=0%, n=4) for respiratory disease, 0.49 (0.23 to 1.05; I2=85%, n=4) for diabetes, 0.74 (0.56 to 0.96; I2=0%, n=3) for infectious diseases, 1.15 (0.66 to 2.02; I2=79%, n=2) for diseases of the nervous system disease, and 0.78 (0.75 to 0.82; I2=0%, n=5) for all non-cardiovascular, non-cancer causes. Reductions in risk were observed up to an intake of 210-225 g/day (seven to seven and a half servings per day) for most of the outcomes. Intakes of specific types of whole grains including whole grain bread, whole grain breakfast cereals, and added bran, as well as total bread and total breakfast cereals were also associated with reduced risks of cardiovascular disease and/or all cause mortality, but there was little evidence of an association with refined grains, white rice, total rice, or total grains.

The authors defined one serving of all grains or whole or refined grains as 30 g, equivalent to one slice of bread or one serving of breakfast cereal. The researchers defined a serving of pasta as 150 g, and a serving of white or brown rice as 167.25 g. They studied changes in the risk for illness or mortality per 90-g increase in whole grain intake and between the lowest and highest intakes, up to 210 to 225 g (7 – 7.5 servings) per day.  The summary relative risk for coronary heart disease for high vs low whole grain consumption was 0.79 (P heterogeneity = 0.63; n = 7 studies), equivalent to a risk reduction of 21%. For stroke, the pooled relative risk for high vs low intake was 0.87 (P heterogeneity = .21; n = 6 studies), a risk reduction of 13%. High vs low whole grain intake also was associated with a 16% reduction in the risk for cardiovascular disease (summary relative risk, 0.84; P heterogeneity = .48; n = 10 studies). In a similar comparison for total cancer, the summary relative risk was 0.89 (P heterogeneity = .003; n = 6 studies), and for all-cause mortality, the pooled relative risk was 0.82 (P heterogeneity < 0.001; n = 11 studies), translating into risk reductions of 11% and 18%, respectively.

In the dose–response analyses, the summary relative risk for coronary heart disease per 90 g/day was 0.81 (n = 7 studies), or a 19% reduction in risk. The summary relative risk for stroke per 90 g/day was 0.88 (n = 6), equivalent to a 12% risk reduction. For cardiovascular disease, the summary relative risk was 0.78 (n = 10) or a 22% risk reduction per 90 g/day. Total cancer was associated with a summary relative risk per 90 g/day of 0.85 (P heterogeneity = .16), a 15% reduction in risk. The summary relative risk for all-cause mortality per 90 g/day was 0.83 (P heterogeneity < .001), a reduction of 17%.

The authors also observed reductions of 19%, 36%, 20%, and 21%, respectively, in the relative risk for mortality from respiratory disease, diabetes, infectious disease, and all deaths not related to cancer or cardiovascular disease between high and low intakes of whole grains. Most of the studies showed “a clear dose-response relation with further reductions with intakes up to seven to seven and a half servings a day (210-225 g/day),” the authors write. These findings suggest that “even moderate increases in whole grain intake could reduce the risk of premature mortality.”

Take great care not to promote whole grain foods with high sugar and salt content.

Whole grains and public health

Whole grain consumption and risk of cardiovascular disease, cancer, and all cause and cause specific mortality systematic review and dose-response meta-analysis of prospective studies

The findings support dietary recommendations to increase intake of whole grains and as much as possible to choose whole grains rather than refined grains.






Ketogenic Diet Data –

The Ketogenic Diet

There have been anecdotal reports of the efficacy of dietary
therapy, especially starvation, for the treatment of epilepsy
since Biblical times. Clinical and
research interest in the ketogenic diet was renewed in the
early 1990s after a 2-year-old boy with intractable seizures
was treated with the ketogenic diet at the Johns Hopkins
Hospital. The diet is now well established in the
medical community and is even reimbursed by insurance
companies, including Blue Cross and Blue Shield. The main indication for the ketogenic diet is the presence of seizures that are difficult to control, such as those that occur in Lennox-Gastaut syndrome. However, the efficacy of the diet appears to be independent of seizure type.

Therapeutic Success of the Ketogenic Diet as a Treatment Option for Epilepsy a Meta-analysis.

Maydell BV, Wyllie E, Akhtar N, et al. Efficacy of the ketogenic diet
in focal versus generalized seizures. Pediatr Neurol. 2001;25:208 –212.   Abstract: 

Most reports of the ketogenic diet have focused on its efficacy for generalized seizures. Few data are available regarding its effect on focal seizures. We retrospectively studied patients (mean = 7.5 years of age) with medically intractable epilepsy treated by the ketogenic diet. The predominant seizure types in each patient were classified as generalized (100 patients) or focal (34 patients) based on ictal electroencephalograms (EEGs) or seizure semiology and interictal EEG. A seizure reduction of more than 50% compared with baseline was seen in nine patients (27%) with focal seizures and 46 patients (46%) with generalized seizures at 3 months, in 10 patients (30%) with focal seizures and 46 patients (46%) with generalized seizures at 6 months, and in eight patients (24%) with focal seizures and 42 patients (42%) with generalized seizures at 12 months. Differences were not significant. Outcome tended to be better in patients younger than 12 years of age compared with the older age group, but the difference was significant at 6 months only. Our results suggest that some patients with intractable focal epilepsy may respond favorably to the ketogenic diet and that this option should be considered if epilepsy surgery is not possible. 

Because the ketogenic diet is associated with major
shifts in cerebral energy metabolism, some authors caution
against using the diet in patients with certain metabolic
disorders. These include pyruvate carboxylase deficiency,
mitochondrial disorders, and fatty acid oxidation problems. 

The actual dietary components are individually calculated
for each patient, incorporating both daily calories,
fluids, and the ratio of fat to protein and carbohydrates,
ranging from 2:1 to 4:1, with higher ratios more restrictive. Young children and infants as well as adolescents are typically started on a 3:1 ratio to be able to provide extra protein and to allow adolescents
increased choices of foods. Most other children are
started on a 4:1 ratio. This is treatment for epilepsy. carbohydrates are typically 5 to 10 g/day, with the remainder of calories as fat. Although fluids and calories are traditionally restricted to improve ketosis, there is little evidence regarding the necessity of this. Older children are given computergenerated
menus that offer 3 daily meals and a snack. Fluids are usually also restricted to 80% of daily needs. There are
some data to suggest that the initial period of fasting is not
necessary for long-term ketosis and that the diet can be
initiated at home without hospitalization. Is a Fast Necessary When Initiating the ketogenic diet Acute problems periodically seen during fasting include hypoglycemia, vomiting, dehydration, and food refusal.
The patient’s medications are also reviewed and adjusted
during the admission to make sure that they are free of
carbohydrates as many, especially liquids, have high carbohydrate
content that can interfere with ketosis.

Seizures Decrease Rapidly After Fasting – preliminary studies of the ketogenic diet

Another version of the ketogenic diet, based on
medium-chain triglyceride (MCT) oil, was developed in the
late 1960s.22 The motivation for development of this diet was
that MCT oils are more strongly ketogenic than longer fatty
acids. This reduces the amount of fat that is required in the
diet, allowing a larger amount of protein and even carbohydrates.
This version of diet, however, can cause gastrointestinal
distress in patients (stomach cramps and diarrhea) and is
used now only occasionally. MCT oil is often incorporated in
the classic ketogenic diet for a variety of reasons, including
increasing the protein and carbohydrate allowances, countering
constipation, or improving dyslipidemia. The medium chain triglyceride diet and intractable epilepsy.

Maintenance of the diet is difficult and common culprits of sugar are new medications or food additives that are labeled as “sugar free” but may still contain large amounts of carbohydrates such as maltodextrin, sorbitol, starch, or fructose. If ketones are not 4 or more than 160 mg/dL, then a 24-hour fast with clear liquids can be used to improve ketosis rapidly.

Acidosis is a major concern during both diet initiation and
acute intercurrent illnesses. It is important that the patient and
family understand signs of acidosis and how to hydrate with
carbohydrate-free fluids. Most children on the diet have a low
baseline acidosis, with HCO3 – of 12 to 18 mg/dL. The issue of whether carnitine supplementation should be used (or acylcarnitine levels checked) is still controversial. COmmon symptoms on the diet are:
Nausea/vomiting during initiation
Weight loss
Constipation (classic diet)
Diarrhea (MCT version)

The incidence of renal calculi in children on the ketogenic
diet is 5 to 6%.27,28 The diet can cause hypercalciuria,
urine acidification, and hypocitraturia, increasing the risk of
uric acid and, less commonly, calcium phosphate and oxalate
stones. Increased hydration and oral polycitrates (Polycitra K™, 2 mEq/kg/day divided twice daily) if there is a family or personal history of kidney stones.

Another known side effect is hyperlipidemia.29–31 A
prospective study of children on the classic diet showed
significant elevations of total cholesterol, triglycerides, and
the atherogenic apolipoprotein B containing lipoproteins
(LDL and VLDL). There was a significant reduction of the
antiatherogenic apolipoprotein A-containing lipoproteins

Long-term monitoring of the ketogenic diet

Manipulation of Types of Fats and Cholesterol Intake Can Successfully Improve the Lipid Profile While Maintaining the Efficacy of the Ketogenic Diet

More fat and fewer seizures dietary therapies for epilepsy

Long-term health consequences of epilepsy

Ketogenic Therapies and Recipes Link << Excellent  < Ketogenic treatment of epilepsy Calorie counter and Carbohydrate trackers Ketogenic diet supplement

Ketocal Supplement PDF guide

Ketogenic Diet Nutritionals

Prospective Study of the Modified Atkins diet and ketogenic supplement during initial month  < Atkins Diet resource

Typical day of food for a child on a 4:1 ratio, 1500 calorie ketogenic diet:

Breakfast: Egg with Bacon Egg 28g Bacon 11g 36% heavy whipping cream 37g Butter 23g Apple 9g

Snack: Peanut Butter Ball Peanut Butter 6g Butter 9g

Lunch: Tuna Salad Tuna fish 28g Mayonnaise 30g Celery 10g 36% heavy whipping cream 36g Lettuce 15g Snack: Keto Yogurt 36% heavy whipping cream 18g Sour Cream 17g Strawberries 4g Artificial sweetener (e.g. Splenda™)

Dinner: Cheeseburger Ground beef 22g American cheese 10g Butter 26g Cream 38g Lettuce 10g Green beans 11g Snack: Keto Custard 36% heavy whipping cream 25g Egg 9g Pure vanilla flavoring

Creative Management of the ketogenic diet and diet therapies

 Ketogenic diet protocol at Johns Hopkins Hospital

Day prior to admission (Sunday)

• Reduced carbohydrates for 24 hours • Fasting starts the evening before admission

Day 1 (Monday) • Admitted to the hospital • Fasting continues • Fluids restricted to 60–75 mL/kg • Blood glucose monitored every 6 hours • Use carbohydrate-free medications • Parents begin educational program

Day 2 (Tuesday) • Dinner, given as “eggnog,” providing 1/3 of calculated maintenance dinner calorie allowance • Blood glucose checks discontinued after dinner • Parents begin to check urine ketones periodically • Education continues

Day 3 (Wednesday) • Breakfast and lunch given as eggnog, providing 1/3 of maintenance breakfast and lunch calorie allowance • Dinner (still eggnog), increased to 2/3 of maintenance dinner calorie allowance • Education continues ·

Day 4 (Thursday) • Breakfast and lunch given as 2/3 of maintenance meal allowance • Dinner is first full ketogenic meal (not eggnog) • Education completed

Day 5 (Friday) • Full ketogenic diet breakfast (calories) given • Prescriptions reviewed and follow-up arranged • Child discharged to home

Modified Atkins Diet Protocol (22) • Copy of a carbohydrate counting guide provided to the family • Carbohydrates described in detail and restricted to 10 grams per day for the first month • Fats (e.g., 36% heavy whipping cream, oils, butter, mayonnaise) encouraged • Clear, carbohydrate-free, fluids and calories not restricted • Low-carbohydrate multivitamin (Unicap M™) and calcium (Calcimix™) supplementation prescribed • Urine ketones checked semiweekly and weight weekly • Medications unchanged for at least the first month, but changed if necessary to tablet or sprinkle (non liquid) preparations • Low-carbohydrate, store-bought products (e.g., shakes, candy bars, baking mixes) discouraged for at least the first month • Complete blood count, complete metabolic profile (SMA-20), fasting lipid profile, urine calcium, and urine creatinine obtained at baseline, 3, and 6 months

Alzheimers and ketotic diet references

β-hydroxybutyrate much more than a metabolite.

Essential roles of four-carbon backbone chemicals in the control of metabolism

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

Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor.

Abstract: Concentrations of acetyl–coenzyme A and nicotinamide adenine dinucleotide (NAD+) affect histone acetylation and thereby couple cellular metabolic status and transcriptional regulation. We report that the ketone body d-β-hydroxybutyrate (βOHB) is an endogenous and specific inhibitor of class I histone deacetylases (HDACs). Administration of exogenous βOHB, or fasting or calorie restriction, two conditions associated with increased βOHB abundance, all increased global histone acetylation in mouse tissues. Inhibition of HDAC by βOHB was correlated with global changes in transcription, including that of the genes encoding oxidative stress resistance factors FOXO3A and MT2. Treatment of cells with βOHB increased histone acetylation at the Foxo3a and Mt2 promoters, and both genes were activated by selective depletion of HDAC1 and HDAC2. Consistent with increased FOXO3A and MT2 activity, treatment of mice with βOHB conferred substantial protection against oxidative stress.

Per the article: Cellular metabolites such as acetyl–coenzyme A (acetyl-CoA) and nicotinamide adenine dinucleotide (NAD+ ) influence gene expression by serving as cofactors for epigenetic modifiers that mediate posttranslational modification of histones . The activity of histone acetyltransferases (HATs) is dependent on nuclear acetyl-CoA concentrations  and the deacetylase activity of class III HDACs, also called sirtuins, is dependent on NAD+ concentrations (4). Class I (HDAC1, 2, 3, 8), class II (HDAC4, 5, 6, 7, 9, 10), and class IV (HDAC11) HDACs are zincdependent enzymes, but endogenous regulators are not known. Small-molecule inhibitors of class I and class II HDACs include butyrate, a product of bacterial anaerobic fermentation (5). Butyrate is closely related to b-hydroxybutyrate (bOHB) (Fig. 1A), the major source of energy for mammals during prolonged exercise or starvation (6). Accumulation of bOHB in blood increases to 1 to 2 mM during fasting when the liver switches to fatty acid oxidation (7, 8), and to even higher concentrations during prolonged fasting (6 to 8 mM) – To determine whether bOHB might have HDAC inhibitor activity was the goal in the article.Our observation that bOHB is an endogenous HDAC inhibitor present in organisms at millimolar concentrations during prolonged fasting and CR reveals an example of integration between metabolic status and epigenetic changes. We show that changes in histone acetylation and gene expression caused by bOHB promote stress resistance in the kidney.For example, low-carbohydrate diets that induce substantial ketogenesis are broadly neuroprotective and enhance resistance of neurons to oxidative damage Ketone bodies are protective against oxidative stress in neocortical neurons. In addition, reduction in HDAC activity by either genetic manipulation or chemical inhibition extends life span in Drosophila Longevity Regulation by Drosophila Rpd3 Deacetylase and Caloric Restriction and Life extension in Drosophila by feeding a drug  Inhibition of HDACs by bOHB might contribute to the beneficial effect of ketogenic diets and may be one mechanism by which calorie restriction confers health benefits.  Finding Ponce de Leon’s Pill Challenges in Screening for Anti-Aging Molecules and Interventions to Slow Aging in Humans Are We Ready and Caloric restriction and its mimetics.

Insulin, ketone bodies and mitcohondrial energy transduction

Thematic Review Series_ Calorie Restriction and Ketogenic Diets_ Ketone ester effects on metabolism and transcription

Thematic Review Series_ Calorie Restriction and Ketogenic Diets_ Ketone Strong_ Emerging evidence for a therapeutic role of ketone bodies in neurological and neurodegenerative diseases b

Very-low-carbohydrate ketogenic diet v. low-fat diet for long-term weight loss = meta-analysis

Abstract: The role of very-low-carbohydrate ketogenic diets (VLCKD) in the long-term management of obesity is not well established. The present meta-analysis aimed to investigate whether individuals assigned to a VLCKD (i.e. a diet with no more than 50 g carbohydrates/d) achieve better long-term body weight and cardiovascular risk factor management when compared with individuals assigned to a conventional lowfat diet (LFD; i.e. a restricted-energy diet with less than 30 % of energy from fat). Through August 2012, MEDLINE, CENTRAL, ScienceDirect, Scopus, LILACS, SciELO, and grey literature databases were searched, using no date or language restrictions, for randomised controlled trials that assigned adults to a VLCKD or a LFD, with 12 months or more of follow-up. The primary outcome was body weight. The secondary outcomes were TAG, HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C), systolic and diastolic blood pressure, glucose, insulin, HbA1c and C-reactive protein levels. A total of thirteen studies met the inclusion/exclusion criteria. In the overall analysis, five outcomes revealed significant results. Individuals assigned to a VLCKD showed decreased body weight (weighted mean difference 20·91 (95 % CI 21·65, 20·17) kg, 1415 patients), TAG (weighted mean difference 20·18 (95 % CI 20·27, 20·08) mmol/l, 1258 patients) and diastolic blood pressure (weighted mean difference 21·43 (95 % CI 22·49, 20·37) mmHg, 1298 patients) while increased HDL-C (weighted mean difference 0·09 (95 % CI 0·06, 0·12) mmol/l, 1257 patients) and LDL-C (weighted mean difference 0·12 (95 % CI 0·04, 0·2) mmol/l, 1255 patients). Individuals assigned to a VLCKD achieve a greater weight loss than those assigned to a LFD in the long term; hence, a VLCKD may be an alternative tool against obesity.  

Other areas of interest in ketotic diets:

Treatment of Parkinson disease with diet-induced hyperketonemia A feasibility study

Abstract:  Patients with idiopathic Parkinson disease (PD) may suffer from impairment of complex I activity involving—but not limited to—dopaminergic neurons of the substantia nigra pars compacta (SNpc).1 The resulting mitochondrial dysfunction could help explain some of the clinical manifestations of the illness. A recent study of isolated mouse brain mitochondria exposed to the complex I inhibitor, 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP), found that mitochondrial oxygen consumption and adenosine triphosphate (ATP) production were significantly increased when D--hydroxybutyrate (DHB) was added to the preparation, apparently by a complex II-dependent mechanism.2 These findings in mice suggested that dietinduced elevation of blood ketones (DHB and acetoacetate [AcAc]) to concentrations sufficient to replace a substantial proportion of glucose as the brain’s fuel might bring about symptomatic improvement in patients with PD by bypassing the presumed complex I defect and boosting mitochondrial function and ATP production. In addition, in vitro and in vivo evidence that DHB protects against MPTP-induced neurotoxicity2,3 suggests that sufficiently prolonged nutritional hyperketonemia might also help delay the progression of idiopathic PD. To increase blood ketones to concentrations within the “therapeutic” range (2 to 7 mmol/L), patients are usually maintained on a “4:1 hyperketogenic diet” (HKD), consisting (by weight) of 4 parts fat and 1 part of a carbohydrate-protein mixture).4 Although this kind of diet has been used successfully for decades for treatment of children and adults with medication-resistant seizure disorders,5 it is difficult to follow; moreover, after prolonged use, significant elevations may occur in serum low-density lipoprotein (LDL) cholesterol and other potentially atherogenic serum lipids.6 Given evidence that ketones crossing the bloodbrain barrier may bypass or compensate for the defect in complex I activity implicated in PD, it seemed desirable to test whether a HKD can benefit patients with PD. However, before attempting an extensive outpatient study, we deemed it essential to determine in a small series whether: 1) ambulatory patients with PD would be able to prepare a HKD in their own homes and remain on it for at least 4 weeks; 2) substitution of mono- and polyunsaturated fats for saturated fats, wherever possible, would mitigate the increases in the serum total cholesterol concentration expected from a very high fat diet; 3) evidence could be obtained to support the clinical safety of the HKD approach in the patients with PD. At best, the improved scores support the safety of the HKD approach. A placebo effect on UPDRS scores has been documented in numerous pharmacologic trials in PD10 and could have occurred in our patients. The studies of isolated mouse brain mitochondria exposed to MPTP, referred to earlier,2 found that ketone supplementation increases the generation of reactive oxygen species, thought by many to be a key mediator of nigral neuron degeneration. This observation is a cause for concern; however, the same investigation also showed DHB to be neuroprotective in the presence of MPTP. Moreover, despite extensive experience with HKDs for treatment of drugresistant epilepsy, there have been no reports of neurodegeneration attributable to diet-induced hyperketonemia sustained for many years.  Ketone Bodies, Potential Therapeutic Uses  –   d-β-Hydroxybutyrate protects neurons in models of Alzheimer’s and Parkinson’s disease   –    

The Therapeutic Potential of the Ketogenic Diet in Treating Progressive Multiple Sclerosis.

A ketogenic diet has been shown to reduce the generation of reactive oxygen species through its effect on uncoupling proteins. It also increases levels of antioxidant agents including catalase and glutathione through its inhibitory action on histone deacetylases and activation of the Nrf2 pathway. 9.1. The Ketogenic Diet Increases Mitochondrial Uncoupling Protein Levels. The process of oxidative phosphorylation generates reactive oxygen species. The extent of reactive oxygen species generation correlates strongly with the potential difference across the inner mitochondrial membrane. Uncoupling proteins (UCPs) can reduce this potential difference by allowing the entry of protons into the mitochondrial matrix. Although this “mild” uncoupling may incur a small reduction in ATP generated through oxidative phosphorylation, its overall net effect is to enhance respiration and ATP levels through a reduction in reactive oxygen species formation and protection from apoptotic events [64]. A ketogenic diet appears to promote UCP activity, specifically the activity of UCP2, UCP4, and UCP5 with a corresponding decline in reactive oxygen species [65]. 9.2. Ketones Inhibit Histone Deacetylases. The ketone betahydroxybutyrate has a direct, dose-dependent inhibitory activity on class I histone deacetylases (HDACs) including HDAC1, HDAC3, and HDAC4. The ketone acetoacetate has also been shown to inhibit class I and class IIa HDACs. Beta-hydroxybutyrate’s inhibition of HDAC promotes the acetylation of histone H3 lysine 9 and histone H3 lysine 14 and increases the transcription of genes regulated by FOXO3A. These include genes leading to the expression of the antioxidant enzymes mitochondrial superoxide dismutase and catalase [66]. 9.3. A Ketogenic Diet Leads to the Activation of the Nrf2 Pathway. The ketogenic diet raises glutathione levels in the hippocampus of rats [67]. This is thought to occur through the Nrf2 (nuclear factor erythroid 2-related factor) pathway. When the ketogenic diet is first initiated, there is a temporary increase in oxidative stress.This may be activating Nrf2, since, a week after the temporary rise in oxidative stress, there is increased expression of Nrf2. Three weeks after the start of the diet, oxidative stress declines to below baseline levels and Nrf2 remains raised. the diet, oxidative stress declines to below baseline levels and Nrf2 remains raised [68]. 10. The Effect of the Ketogenic Diet on ATP Levels A ketogenic diet enhances ATP production. The administration of beta-hydroxybutyrate immediately following bilateral common carotid artery ligation in a mouse model of global cerebral ischaemia preserves ATP levels [69]. Feeding mice a ketogenic diet for three weeks resulted in increased levels of ATP and the ATP/ADP ratio in the brain [70]. The improvement in ATP levels may partly be explained through the ability of the ketogenic diet to reduce oxidative stress. Although the diet may reduce reactive oxygen species generation through an increase in UCP activity, any reduction in oxidative phosphorylation incurred through UCP activity is outweighed by the enhancement of respiration and associated ATP production occurring as a result of reduced oxidative stress. A ketogenic diet also appears to preserve ATP levels in the event of mitochondrial respiratory chain dysfunction, possibly through the replenishment of TCA cycle intermediates [71]. Beta-hydroxybutyrate attenuates the decrease in ATP production caused by a defect in complex I of the electron transport chain. It is thought to increase levels of the TCA intermediate succinate, which bypasses complex I when entering the TCA cycle [65, 72]. This carries considerable implications for MS, since defects in complex I within the electron transport chain have been observed in white matter lesions as well as in “normal” regions of the motor cortex [39, 73]. Ketones can also preserve ATP levels if complex II of the electron transport chain is inhibited, but this effect shows some regional specificity [74]. 11. The Effect of the Ketogenic Diet on Mitochondrial Biogenesis Mitochondrial biogenesis within the rat hippocampus and cerebellar vermis is increased by the ketogenic diet [75, 76]. Although the precise pathway for this is not known, it is thought to involve the PGC1? family of transcriptional coactivators, which promote transcription factors including NRF-1, NRF-2, and ERR? [77]. 12. The Effect of the Ketogenic Diet on Inflammation The anti-inflammatory effect of a ketogenic diet has been demonstrated in a murine model of lipopolysaccharideinduced fever [78]. In a rat model of MS, the diet suppressed the expression of inflammatory cytokines and enhanced CA1 hippocampal synaptic plasticity and long-term potentiation, which resulted in improved learning, memory, and motor ability [79]. The anti-inflammatory effect of a ketogenic diet may partly be explained through the inhibition of the NLRP3 inflammasome by beta-hydroxybutyrate in a manner that is independent of starvation-induced mechanisms such as AMPK, autophagy, or glycolytic inhibition. The NLRP3 inflammasome is responsible for the cleavage of procaspase-1 into caspase-1 and the activation of the cytokines IL-1? and IL-18. Its inhibition prevents IL-1? and IL-18 generation and their downstream effects [80]. 13. The Neuroprotective Properties of the Ketogenic Diet Ketone bodies play a neuroprotective role in animal models of neurodegeneration [69, 81]. ATP-sensitive potassium channels (K ATP channels) located on the cell surface of neurons stabilize neuronal excitability. Ketones promote an “open state” of these channels and confer neuronal stability [82]. K ATP channels also play a role in mitochondrial function and in cell death. The “open state” of K ATP channels located on the inner mitochondrial membrane prevents the formation of mitochondrial permeability transition pores (MPTPs) that can lead to mitochondrial swelling and cell death. Acetoacetate and beta-hydroxybutyrate have been shown to increase the threshold for calcium-induced MPTP formation [83]. 14. The Regional Variation of the Effect of Ketones in the Mouse Cerebellum Despite these seemingly positive effects on mitochondrial bioenergetics, the effects of a ketogenic diet on mitochondria within the mouse brain are not homogenous and some results appear conflicting. Although the study on the murine model of EAE demonstrated improved CA1 synaptic plasticity, in another study, on rats, although a KD prevented age-related morphological changes within the outer layer of the dentate gyrus of the cerebellum, it produced negative changes within the CA1 region [84]. In a study on rats fed a ketogenic diet for 8 weeks, antioxidant status was elevated within the hippocampus but not in the cerebral cortex and antioxidant activity was seen to be reduced within the cerebellum.Despite its high fat component, the ketogenic diet is safe and even beneficial for cardiometabolic risk factors [90]. It has been in continuous use for almost a century for the treatment of epilepsy and has shown good tolerability, even in children [91]. Current ketogenic diet protocols involve a range of options, which encourages patient compliance. Where compliance may pose a challenge, mimicry of various components of the ketogenic pathway through the use of ketone analogues may offer a palatable therapeutic option [92]. Supplementation with ketones to induce ketosis has also shown an acceptable safety and tolerability profile [93].

Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects and The ketogenic diet component decanoic acid increases mitochondrial citrate synthase and complex I activity in neuronal cells  <<< safety of Ketogenic diet

Ketogenic Blog  << Blog site

Dietary carbohydrate restriction improves insulin sensitivity, blood pressure, microvascular function, and cellular adhesion markers in individuals taking statins.

Statins positively impact plasma low-density lipoprotein cholesterol, inflammation and vascular endothelial function (VEF). Carbohydrate restricted diets (CRD) improve atherogenic dyslipidemia, and similar to statins, have been shown to favorably affect markers of inflammation and VEF. No studies have examined whether a CRD provides additional benefit beyond that achieved by habitual statin use. We hypothesized that a CRD (<50 g carbohydrate/d) for 6 weeks would improve lipid profiles and insulin sensitivity, reduce blood pressure, decrease cellular adhesion and inflammatory biomarkers, and augment VEF (flow-mediated dilation and forearm blood flow) in statin users. Participants (n = 21; 59.3 ± 9.3 y, 29.5 ± 3.0 kg/m2 ) decreased total caloric intake by approximately 415 kcal at 6 weeks (P < .001). Daily nutrient intakes at baseline (46/36/17% carb/fat/pro) and averaged across the intervention (11/58/28% carb/fat/pro) demonstrated dietary compliance, with carbohydrate intake at baseline nearly 5-fold greater than during the intervention (P < .001). Compared to baseline, both systolic and diastolic blood pressure decreased after 3 and 6 weeks (P < .01). Peak forearm blood flow, but not flow-mediated dilation, increased at week 6 compared to baseline and week 3 (P ≤ .03). Serum triglyceride, insulin, soluble E-Selectin and intracellular adhesion molecule-1 decreased (P < .01) from baseline at week 3, and this effect was maintained at week 6. In conclusion, these findings demonstrate that individuals undergoing statin therapy experience additional improvements in metabolic and vascular health from a 6 weeks CRD as evidenced by increased insulin sensitivity and resistance vessel endothelial function, and decreased blood pressure, triglycerides, and adhesion molecules. 

Potential Therapeutic Use of the Ketogenic Diet in Autism Spectrum Disorders  < consideration for use in Autism  —> I also add this: Gastrointestinal dysfunction in autism spectrum disorder the role of the mitochondria and the enteric microbiome and this Enteric short-chain fatty acids microbial messengers of metabolism, mitochondria, and mind implications in autism spectrum disorders

Of interest re: SCFA : Cocobiota Implications for Human Health.  << Current advances in molecular microbiology and analytical food chemistry suggest that processed cocoa beans and cocoa-based products may contain some substances and chemical compounds of microbial and fungal origin which are highly beneficial to human health. Taking into consideration the obvious significance of bacterial and fungal species in the process of fermentation of cocoa beans as well as their potential impact on human health, we introduce herein a new term COCOBIOTA. We define cocobiota as a specific unity of bacteria and fungi which drives spontaneous postharvest fermentation of cocoa beans and which may have some health effect through various primary and secondary metabolites of bacterial-fungal origin present in cocoa powder and dark chocolate

Moody microbes or fecal phrenology what do we know about the microbiota-gut-brain axis  << Microbiome and SCFA related behaviors

Reversal of Diabetic Nephropathy by a Ketogenic Diet  <<< Intensive insulin therapy and protein restriction delay the development of nephropathy in a variety of conditions, but few interventions are known to reverse nephropathy. Having recently observed that the ketone 3-beta-hydroxybutyric acid (3-OHB) reduces molecular responses to glucose, we hypothesized that a ketogenic diet, which produces prolonged elevation of 3-OHB, may reverse pathological processes caused by diabetes. To address this hypothesis, we assessed if prolonged maintenance on a ketogenic diet would reverse nephropathy produced by diabetes. In mouse models for both Type 1 (Akita) and Type 2 (db/db) diabetes, diabetic nephropathy (as indicated by albuminuria) was allowed to develop, then half the mice were switched to a ketogenic diet. After 8 weeks on the diet, mice were sacrificed to assess gene expression and histology. Diabetic nephropathy, as indicated by albumin/creatinine ratios as well as expression of stress-induced genes, was completely reversed by 2 months maintenance on a ketogenic diet. However, histological evidence of nephropathy was only partly reversed. These studies demonstrate that diabetic nephropathy can be reversed by a relatively simple dietary intervention. Whether reduced glucose metabolism mediates the protective effects of the ketogenic diet remains to be determined.

The Effect of a Low-Carbohydrate, Ketogenic Diet on Nonalcoholic Fatty Liver Disease A Pilot Study   << Abstract Nonalcoholic fatty liver disease is an increasingly common condition that may progress to hepatic cirrhosis. This pilot study evaluated the effects of a low-carbohydrate, ketogenic diet on obesity-associated fatty liver disease. Five patients with a mean body mass index of 36.4 kg/m2 and biopsy evidence of fatty liver disease were instructed to follow the diet (<20 g/d of carbohydrate) with nutritional supplementation for 6 months. Patients returned for group meetings biweekly for 3 months, then monthly for the second 3 months. The mean weight change was − 12.8 kg (range 0 to − 25.9 kg). Four of 5 posttreatment liver biopsies showed histologic improvements in steatosis (P = .02) inflammatory grade (P = .02), and fibrosis (P = .07). Six months of a lowcarbohydrate, ketogenic diet led to significant weight loss and histologic improvement of fatty liver disease. Further research is into this approach is warranted. 

Also: Middle and Long-Term Impact of a Very Low-Carbohydrate Ketogenic Diet on Cardiometabolic Factors A Multi-Center, Cross-Sectional, Clinical Study.   Results All the predetermined goals—namely safety, reduction of body weight and CV risk factors levels—have been reached with a significant reduction of body weight (from baseline to 4 weeks (-7 ± 5 kg, p\0.001), from 4 to 12 weeks (-5 ± 3 kg, p\0.001), no changes from 12 weeks to 12 months; waistline (from baseline to 4 weeks (-7 ± 4 cm, p\0.001), from 4 to 12 weeks (-5 ± 7 cm, p\0.001), no changes from 12 weeks to 12 months; fatty mass (from baseline to 4 weeks (-3.8 ± 3.8 %, p\0.001), from 4 to 12 weeks (-3.4 ± 3.5 %, p\0.001), no changes from 12 weeks to 12 months; SBP from baseline to 3 months (-10.5 ± 6.4 mmHg, p\0.001), no further changes after 1 year of observation). Conclusion the tested VLCD diet suggested by trained general physicians in the setting of clinical practice seems to be able to significantly improve on the middle-term a number of anthropometric, haemodynamic and laboratory with an overall good tolerability. 

Middle and Long-Term Impact of a Very Low-Carbohydrate Ketogenic Diet on Cardiometabolic Factors A Multi-Center, Cross-Sectional, Clinical Study.   CONCLUSION:  the tested VLCD diet suggested by trained general physicians in the setting of clinical practice seems to be able to significantly improve on the middle-term a number of anthropometric, haemodynamic and laboratory with an overall good tolerability.

Beyond weight loss- a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets.  <<< Very-low-carbohydrate diets or ketogenic diets have been in use since the 1920s as a therapy for epilepsy and can, in some cases, completely remove the need for medication. From the 1960s onwards they have become widely known as one of the most common methods for obesity treatment. Recent work over the last decade or so has provided evidence of the therapeutic potential of ketogenic diets in many pathological conditions, such as diabetes, polycystic ovary syndrome, acne, neurological diseases, cancer and the amelioration of respiratory and cardiovascular disease risk factors. The possibility that modifying food intake can be useful for reducing or eliminating pharmaceutical methods of treatment, which are often lifelong with significant side effects, calls for serious investigation. This review revisits the meaning of physiological ketosis in the light of this evidence and considers possible mechanisms for the therapeutic actions of the ketogenic diet on different diseases. The present review also questions whether there are still some preconceived ideas about ketogenic diets, which may be presenting unnecessary barriers to their use as therapeutic tools in the physician’s hand.

Ketosis, ketogenic diet and food intake control a complex relationship l    Though the hunger-reduction phenomenon reported during ketogenic diets is well-known, the underlying molecular and cellular mechanisms remain uncertain. Ketosis has been demonstrated to exert an anorexigenic effect via cholecystokinin (CCK) release while reducing orexigenic signals e.g., via ghrelin. However, ketone bodies (KB) seem to be able to increase food intake through AMP-activated protein kinase (AMPK) phosphorylation, gamma-aminobutyric acid (GABA) and the release and production of adiponectin. The aim of this review is to provide a summary of our current knowledge of the effects of ketogenic diet (KD) on food control in an effort to unify the apparently contradictory data into a coherent picture.

Effect of Ketogenic Mediterranean diet with phytoextracts and low CHO-high protein meals  << The KEMEPHY diet lead to weight reduction, improvements in cardiovascular risk markers, reduction in waist circumference and showed good compliance.

Ketogenic Diet in Neuromuscular and Neurodegenerative Diseases  An increasing number of data demonstrate the utility of ketogenic diets in a variety of metabolic diseases as obesity, metabolic syndrome, and diabetes. In regard to neurological disorders, ketogenic diet is recognized as an effective treatment for pharmacoresistant epilepsy but emerging data suggests that ketogenic diet could be also useful in amyotrophic lateral sclerosis, Alzheimer, Parkinson’s disease, and some mitochondriopathies. Although these diseases have different pathogenesis and features, there are some common mechanisms that could explain the effects of ketogenic diets. These mechanisms are to provide an efficient source of energy for the treatment of certain types of neurodegenerative diseases characterized by focal brain hypometabolism; to decrease the oxidative damage associated with various kinds of metabolic stress; to increase the mitochondrial biogenesis pathways; and to take advantage of the capacity of ketones to bypass the defect in complex I activity implicated in some neurological diseases. These mechanisms will be discussed in this review. 

High-Fat and Ketogenic Diets in Amyotrophic Lateral Sclerosis  << In summary, there are strong epidemiologic data showing that malnutrition is a common symptom of amyotrophic lateral sclerosis both in humans and in mice and may contribute to disease progression. There is also epidemiologic evidence that increased dietary fat and cholesterol intake might reduce the risk of amyotrophic lateral sclerosis and the rate disease progression. Finally, data from animal studies strongly suggest that increasing dietary intake of fat ameliorates disease progression. However, determining whether amyotrophic lateral sclerosis patients should be treated with a high-fat or ketogenic diet can be based only on randomized double-blind placebo-controlled interventional trials.

Hypercaloric enteral nutrition in patients with amyotrophic lateral sclerosis a randomised, double-blind, placebo-controlled phase 2 trial.





A modified Atkins diet is promising as a treatment for glucose transporter type 1 deficiency syndrome  < use of ketogenic diet in GLUT transporter problems




Beta hydroxybutyrate upregulates genes to prevent oxidative stress as reviewed in the above articles.

8-Volek-Moving Toward a Personalized Approach to Nutrition  << excellent slide show


Metabolic therapeutics and ketogenic diet 2016  << presentation

Limited Effect of Dietary Saturated Fat on Plasma Saturated Fat in the Context of a Low Carbohydrate Diet   A  hypocaloric carbohydrate restricted diet (CRD) had two striking effects: (1) a reduction in plasma saturated fatty acids (SFA) despite higher intake than a low fat diet, and (2) a decrease in inflammation despite a significant increase in arachidonic acid (ARA).These findings are consistent with the concept that dietary saturated fat is efficiently metabolized in the presence of low carbohydrate, and that a CRD results in better preservation of plasma ARA.

A ketogenic diet favorably affects serum biomarkers for cardiovascular disease in normal-weight men. n    Fasting blood lipids, insulin, LDL particle size, oxidized LDL and postprandial triacylglycerol (TAG) and insulin responses to a fat-rich meal were determined before and after treatment. There were significant decreases in fasting serum TAG (-33%), postprandial lipemia after a fat-rich meal (-29%), and fasting serum insulin concentrations (-34%) after men consumed the ketogenic diet.


A Low-Carbohydrate, Whole-Foods Approach to Managing Diabetes and Prediabetes

A Low-Carbohydrate, Whole-Foods Approach to Managing Diabetes and Prediabetes  We recently proposed that the biological markers improved by carbohydrate restriction were precisely those that define the metabolic syndrome (MetS), and that the common thread was regulation of insulin as a control element. We specifically tested the idea with a 12-week study comparing two hypocaloric diets (approximately 1,500 kcal): a carbohydrate-restricted diet (CRD) (%carbohydrate:fat:protein = 12:59:28) and a low-fat diet (LFD) (56:24:20) in 40 subjects with atherogenic dyslipidemia. Both interventions led to improvements in several metabolic markers, but subjects following the CRD had consistently reduced glucose (-12%) and insulin (-50%) concentrations, insulin sensitivity (-55%), weight loss (-10%), decreased adiposity (-14%), and more favorable triacylglycerol (TAG) (-51%), HDL-C (13%) and total cholesterol/HDL-C ratio (-14%) responses. In addition to these markers for MetS, the CRD subjects showed more favorable responses to alternative indicators of cardiovascular risk: postprandial lipemia (-47%), the Apo B/Apo A-1 ratio (-16%), and LDL particle distribution. Despite a threefold higher intake of dietary saturated fat during the CRD, saturated fatty acids in TAG and cholesteryl ester were significantly decreased, as was palmitoleic acid (16:1n-7), an endogenous marker of lipogenesis, compared to subjects consuming the LFD. Serum retinol binding protein 4 has been linked to insulin-resistant states, and only the CRD decreased this marker (-20%). The findings provide support for unifying the disparate markers of MetS and for the proposed intimate connection with dietary carbohydrate. The results support the use of dietary carbohydrate restriction as an effective approach to improve features of MetS and cardiovascular risk.

Effects of exogenous ketone supplementation on blood ketone, glucose, triglyceride, and lipoprotein levels in Sprague-Dawley rats.  :Exogenous ketone supplementation caused a rapid and sustained elevation of βHB, reduction of glucose, and little change to lipid biomarkers compared to control animals.

Comparison of Low Fat and Low Carbohydrate Diets on Circulating Fatty Acid Composition and Markers of Inflammation

Abstract:  Abnormal distribution of plasma fatty acids and increased inflammation are prominent features of metabolic syndrome. We tested whether these components of metabolic syndrome, like dyslipidemia and glycemia, are responsive to carbohydrate restriction. Overweight men and women with atherogenic dyslipidemia consumed ad libitum diets very low in carbohydrate (VLCKD) (1504 kcal:%CHO:fat:protein = 12:59:28) or low in fat (LFD) (1478 kcal:%CHO:fat:protein = 56:24:20) for 12 weeks. In comparison to the LFD, the VLCKD resulted in an increased proportion of serum total n-6 PUFA, mainly attributed to a marked increase in arachidonate (20:4n-6), while its biosynthetic metabolic intermediates were decreased. The n-6/n-3 and arachidonic/eicosapentaenoic acid ratio also increased sharply. Total saturated fatty acids and 16:1n-7 were consistently decreased following the VLCKD. Both diets significantly decreased the concentration of several serum inflammatory markers, but there was an overall greater anti-inflammatory effect associated with the VLCKD, as evidenced by greater decreases in TNF-alpha, IL-6, IL-8, MCP-1, E-selectin, I-CAM, and PAI-1. Increased 20:4n-6 and the ratios of 20:4n-6/20:5n-3 and n-6/n-3 are commonly viewed as pro-inflammatory, but unexpectedly were consistently inversely associated with responses in inflammatory proteins. In summary, a very low carbohydrate diet resulted in profound alterations in fatty acid composition and reduced inflammation compared to a low fat diet.

The above shows that despite being higher in saturated fat, a ketogenic diet decreases circulating levels of saturated fatty acids

Effects of a high-protein ketogenic diet on hunger, appetite, and weight loss in obese men feeding ad libitum

Ketogenic diets and pain.

Drivers of age-related inflammation and strategies for healthspan extension

Ageing Is Associated with Decreases in Appetite and Energy Intake–A Meta-Analysis in Healthy Adults.

Effects of food form on food intake and postprandial appetite sensations, glucose and endocrine responses, and energy expenditure in resistance trained v. sedentary older adults.

Leucine Supplementation and Intensive Training

The Neuropharmacology of the Ketogenic Diet

Gluconeogenesis and energy expenditure after a high-protein, carbohydrate-free diet

Alternat fuel utilization by brain

Telomeres and telomerase as therapeutic targets to prevent and treat age-related diseases.

Exercise Modulates Oxidative Stress and Inflammation in Aging and Cardiovascular Diseases.

Neuro-immune Dysfunction During Brain Agin New Insights in Microglial Cell Regulation

Nutrition and muscle protein synthesis a descriptive review

Endurance Exercise Training Up-Regulates Lipolytic proteins and reduces tg content in skeletal muscle of obese subjects

Acute nutritional ketosis implications for exercise performance and metabolism   <<< Exercise related ketosis

Beneficial effects of ketogenic diet in obese diabetic subjects.  < Excellent study showing sustained weight loss over a year period – also blood lipids improvement were sustained as well using a well-crafted ketogenic diet. Diet guidelines included meat, fish, poultry, full fat cheeses, green vegetables, 5 T/day olive oil, flax seed oil.

Excess carbohydrates taken in above which you can metabolize will be converted to fat. This results in increased circulating levels of saturated fats, especially palimitoleic acid (16:1) and exacerbates insulin resistance.

If you have insulin resistance – restricting sugars and starches can profoundly benefit all risk factors. Insulin resistance is a carbohydrate intolerant state.

Higher levels of palmitoleic acid in the blood stream or adipose tissue are associated with bad outcomes such as: obesity, hypertriglyceridemia, hyperglycemia, inflammation, metabolic syndrome, heart failure, increased incidence of prostate cancer, coronary artery disease, diabetes, etc

Even without high blood sugar, increase pamitoleic acid in the blood is associated with increased risk of developing type 2 diabetes.

Effects of Step-Wise Increases in Dietary Carbohydrate on Circulating Saturated Fatty Acids and Palmitoleic Acid in Adults with Metabolic Syndrome    Recent meta-analyses have found no association between heart disease and dietary saturated fat; however, higher proportions of plasma saturated fatty acids (SFA) predict greater risk for developing type-2 diabetes and heart disease. These observations suggest a disconnect between dietary saturated fat and plasma SFA, but few controlled feeding studies have specifically examined how varying saturated fat intake across a broad range affects circulating SFA levels. Sixteen adults with metabolic syndrome (age 44.9¡9.9 yr, BMI 37.9¡6.3 kg/m2 ) were fed six 3-wk diets that progressively increased carbohydrate (from 47 to 346 g/day) with concomitant decreases in total and saturated fat. Despite a distinct increase in saturated fat intake from baseline to the low-carbohydrate diet (46 to 84 g/day), and then a gradual decrease in saturated fat to 32 g/day at the highest carbohydrate phase, there were no significant changes in the proportion of total SFA in any plasma lipid fractions. Whereas plasma saturated fat remained relatively stable, the proportion of palmitoleic acid in plasma triglyceride and cholesteryl ester was significantly and uniformly reduced as carbohydrate intake decreased, and then gradually increased as dietary carbohydrate was re-introduced. The results show that dietary and plasma saturated fat are not related, and that increasing dietary carbohydrate across a range of intakes promotes incremental increases in plasma palmitoleic acid, a biomarker consistently associated with adverse health outcomes.

Effect of short-term carbohydrate overfeeding and long-term weight loss on liver fat in overweight humans    Background: Cross-sectional studies have identified a high intake of simple sugars as an important dietary factor predicting nonalcoholic fatty liver disease (NAFLD). Objective: We examined whether overfeeding overweight subjects with simple sugars increases liver fat and de novo lipogenesis (DNL) and whether this is reversible by weight loss. Design: Sixteen subjects [BMI (kg/m2 ): 30.6 6 1.2] were placed on a hypercaloric diet (.1000 kcal simple carbohydrates/d) for 3 wk and, thereafter, on a hypocaloric diet for 6 mo. The subjects were genotyped for rs739409 in the PNPLA3 gene. Before and after overfeeding and after hypocaloric diet, metabolic variables and liver fat (measured by proton magnetic resonance spectroscopy) were measured. The ratio of palmitate (16:0) to linoleate (18:2n26) in serum and VLDL triglycerides was used as an index of DNL. Results: Carbohydrate overfeeding increased weight (6SEM) by 2% (1.8 6 0.3 kg; P , 0.0001) and liver fat by 27% from 9.2 6 1.9% to 11.7 6 1.9% (P = 0.005). DNL increased in proportion to the increase in liver fat and serum triglycerides in subjects with PNPLA3-148II but not PNPLA3-148MM. During the hypocaloric diet, the subjects lost 4% of their weight (3.2 6 0.6 kg; P , 0.0001) and 25% of their liver fat content (from 11.7 6 1.9% to 8.8 6 1.8%; P , 0.05). Conclusions: Carbohydrate overfeeding for 3 wk induced a .10-fold greater relative change in liver fat (27%) than in body weight (2%). The increase in liver fat was proportional to that in DNL. Weight loss restores liver fat to normal. These data indicate that the human fatty liver avidly accumulates fat during carbohydrate overfeeding and support a role for DNL in the pathogenesis of NAFLD  

Effects of short-term carbohydrate or fat overfeeding on energy expenditure and plasma leptin concentrations in healthy female subjects

Comparison of low fat and low carbohydrate diets on circulating fatty acid composition and markers of inflammation.   Abnormal distribution of plasma fatty acids and increased inflammation are prominent features of metabolic syndrome. We tested whether these components of metabolic syndrome, like dyslipidemia and glycemia, are responsive to carbohydrate restriction. Overweight men and women with atherogenic dyslipidemia consumed ad libitum diets very low in carbohydrate (VLCKD) (1504 kcal:%CHO:fat:protein = 12:59:28) or low in fat (LFD) (1478 kcal:%CHO:fat:protein = 56:24:20) for 12 weeks. In comparison to the LFD, the VLCKD resulted in an increased proportion of serum total n-6 PUFA, mainly attributed to a marked increase in arachidonate (20:4n-6), while its biosynthetic metabolic intermediates were decreased. The n-6/n-3 and arachidonic/eicosapentaenoic acid ratio also increased sharply. Total saturated fatty acids and 16:1n-7 were consistently decreased following the VLCKD. Both diets significantly decreased the concentration of several serum inflammatory markers, but there was an overall greater anti-inflammatory effect associated with the VLCKD, as evidenced by greater decreases in TNF-alpha, IL-6, IL-8, MCP-1, E-selectin, I-CAM, and PAI-1. Increased 20:4n-6 and the ratios of 20:4n-6/20:5n-3 and n-6/n-3 are commonly viewed as pro-inflammatory, but unexpectedly were consistently inversely associated with responses in inflammatory proteins. In summary, a very low carbohydrate diet resulted in profound alterations in fatty acid composition and reduced inflammation compared to a low fat diet.

Serum saturated fatty acids containing triacylglycerols are better markers of insulin resistance than total serum triacylglycerol concentrations.    results: We identified 45 different TGs in serum. Serum TGs containing saturated and monounsaturated fatty acids were positively, while TGs containing essential linoleic acid (18:2 n-6) were negatively correlated with HOMA-IR. Specific serum TGs that correlated positively with HOMA-IR were also significantly positively related to HOMA-IR when measured in very-low-density lipoproteins (VLDLs), intermediate-density lipoproteins (IDLs) and LDL, but not in HDL subfraction 2 (HDL(2)) or 3 (HDL(3)). Analyses of proportions of esterified fatty acids within lipoproteins revealed that palmitic acid (16:0) was positively related to HOMA-IR when measured in VLDL, IDL and LDL, but not in HDL(2) or HDL(3). Monounsaturated palmitoleic (16:1 n-7) and oleic (18:1 n-9) acids were positively related to HOMA-IR when measured in HDL(2) and HDL(3), but not in VLDL, IDL or LDL. Linoleic acid was negatively related to HOMA-IR in all lipoproteins   Conclusions: Serum concentrations of specific TGs, such as TG(16:0/16:0/18:1) or TG(16:0/18:1/18:0), may be more precise markers of insulin resistance than total serum TG concentrations. 


PLASMA SATURATED FAT Predicts heart Disease

Fatty-acid composition of serum lipids predicts myocardial infarction. Healthy men with higher plasma SFA (16:0 and 18:0) had significantly greater incidience of heart attack.

During a follow-up of five to seven years 33 out of 1222 middle-aged men initially free of coronary heart disease sustained fatal or non-fatal myocardial infarction or died suddenly. The fatty-acid composition of serum triglycerides, phospholipids, and cholesterol esters had been measured at the start of the surveillance in these men and in a control group of 64 men matched for age, serum cholesterol and triglyceride concentrations, blood pressure, obesity, smoking, and one-hour glucose tolerance. Palmitic and stearic acids of phospholipids were significantly higher and linoleic and most polyunsaturated fatty acids, including arachidonic acid and eicosapentaenoic acid, of phospholipids were lower in the subjects who sustained coronary events compared with the controls. Linoleic acid tended to correlate negatively with blood pressure while other polyunsaturated fatty acids, especially eicosapentaenoic acid, exhibited a negative correlation with blood pressure and relative body weight in the controls but not in the subjects who sustained coronary events. These findings suggest that the fatty-acid pattern of serum phospholipids is an independent risk factor for coronary heart disease.

Intake of saturated and trans unsaturated fatty acids and risk of all cause mortality, cardiovascular disease, and type 2 diabetes systematic review and meta-analysis of observational studies.

For saturated fat, three to 12 prospective cohort studies for each association were pooled (five to 17 comparisons with 90,501-339,090 participants). Saturated fat intake was not associated with all cause mortality (relative risk 0.99, 95% confidence interval 0.91 to 1.09), CVD mortality (0.97, 0.84 to 1.12), total CHD (1.06, 0.95 to 1.17), ischemic stroke (1.02, 0.90 to 1.15), or type 2 diabetes (0.95, 0.88 to 1.03). There was no convincing lack of association between saturated fat and CHD mortality (1.15, 0.97 to 1.36; P=0.10). For trans fats, one to six prospective cohort studies for each association were pooled (two to seven comparisons with 12,942-230,135 participants). Total trans fat intake was associated with all cause mortality (1.34, 1.16 to 1.56), CHD mortality (1.28, 1.09 to 1.50), and total CHD (1.21, 1.10 to 1.33) but not ischemic stroke (1.07, 0.88 to 1.28) or type 2 diabetes (1.10, 0.95 to 1.27). Industrial, but not ruminant, trans fats were associated with CHD mortality (1.18 (1.04 to 1.33) v 1.01 (0.71 to 1.43)) and CHD (1.42 (1.05 to 1.92) v 0.93 (0.73 to 1.18)). Ruminant trans-palmitoleic acid was inversely associated with type 2 diabetes (0.58, 0.46 to 0.74). The certainty of associations between saturated fat and all outcomes was “very low.” The certainty of associations of trans fat with CHD outcomes was “moderate” and “very low” to “low” for other associations.


Saturated fats are not associated with all cause mortality, CVD, CHD, ischemic stroke, or type 2 diabetes, but the evidence is heterogeneous with methodological limitations. Trans fats are associated with all cause mortality, total CHD, and CHD mortality, probably because of higher levels of intake of industrial trans fats than ruminant trans fats. Dietary guidelines must carefully consider the health effects of recommendations for alternative macronutrients to replace trans fats and saturated fats.

Serum fatty acids and the risk of coronary heart disease  – [Men who had heart attacks had higher serum palmitic acid (16:0) and a 68% greater risk of heart disease]   To examine the relation between serum fatty acids and coronary heart disease (CHD), the authors conducted a nested case-control study of 94 men with incident CHD and 94 men without incident CHD who were enrolled in the Usual Care group of the Multiple Risk Factor Intervention Trial between December 1973 and February 1976. After confirming the stability of the stored serum samples, the authors measured serum fatty acid levels by gas-liquid chromatography and examined their association with CHD. In all multivariate models, levels of the cholesterol ester saturated fatty acid palmitic acid (16:0) were directly associated with CHD risk (standardized odds ratio = 1.68; 95% confidence interval 1.10-2.55 in the model that adjusted for total plasma cholesterol level). Levels of the phospholipid omega-3 fatty acid docosapentaenoic acid (22:5) were inversely associated with CHD risk in the two multivariate models that controlled for the effects of total plasma cholesterol level or high density lipoprotein cholesterol to total plasma cholesterol ratio (standardized odds ratio = 0.58; 95% confidence interval 0.38-0.89 in the first model that controlled for total plasma cholesterol level). In contrast to the first two multivariate models, levels of the docosahexaenoic acid (22:6) were inversely associated with CHD risk in a third multivariate model that controlled for the effects of high density lipoprotein cholesterol to low density lipoprotein cholesterol ratio (standardized odds ratio = 0.57; 95% confidence interval 0.36-0.90). These findings are consistent with other evidence indicating that saturated fatty acids are directly correlated with CHD and that omega-3 polyunsaturated fatty acids are inversely correlated with CHD. Because these associations were present after adjustment for blood lipid levels, other mechanisms, such as a direct effect on blood clotting, may be involved.

Plasma fatty acid composition and incidence of coronary heart disease in middle aged adults_ the Atherosclerosis Risk in Communities (ARIC) Study  In 282 out of 3591 men who had heart attacks over 11 years, plasma CE and PL SFA’s were higher

To prospectively investigate the relation of plasma cholesterol ester (CE) and phospholipid (PL) fatty acid (FA) composition with incidence of coronary heart disease (CHD).


3,591 white participants in the Minneapolis field center of the Atherosclerosis Risk in Communities Study, aged 45-64 years, were studied. Plasma FA composition of CEs and PLs was quantified using gas-liquid chromatography and expressed as percentage of total FAs. Incident CHD was identified during 10.7 years of follow-up. In both CE and PL fractions, the proportions of stearic (18:0) acid, dihomo-gamma-linolenic (20:3n6) acid and total saturated fatty acids (SFAs) were significantly higher while arachidonic (20:4n6) acid and total polyunsaturated fatty acids (PUFAs) were significantly lower among participants who developed incident CHD (n = 282). After adjusting for age, gender, smoking, alcohol drinking, sports activity, and non-FA dietary factors, the incidence of CHD was significantly and positively associated with the proportion of dihomo-gamma-linolenic acid but inversely associated with arachiadonic acid. The multiply-adjusted rate ratios (RRs) of CHD incidence for the highest versus the lowest quintile were 1.31 in CE and 1.44 in PL for dihomo-gamma-linolenic acid (p for trend: 0.05 and 0.017, respectively), 0.59 in CE and 0.65 in PL for arachidonic acid (p: 0.016 and 0.024, respectively). Also significantly and positively associated with incident CHD were PL stearic acid and CE linolenic (18:3n3) acid. Only a borderline significant positive association was observed for total SFAs in CE (multivariate RRs across quintiles: 1.00, 1.15, 1.40, 1.62, 1.32; p = 0.07). Total PUFAs or monounsaturated FA were not independently associated with CHD.


Our study found a weak positive association of SFAs with incident CHD. Our findings also confirm that FA metabolism in the body, such as the activity of delta-5 desaturase, which converts dihomo-gamma-linolenic acid to arachidonic acid, may affect the development of CHD.

Plasma fatty acid composition and incident heart failure in middle-aged adults the Atherosclerosis Risk in Communities (ARIC) Study IN this study 197 out of 3592 adults who developed heart failure, plasma CE (cholesterol esthers) and PL(phospholipids_ SFAs were higher


Dietary Fat and Coronary Heart Disease summary of evidence from prospective cohort and randomised controlled trials  – No association bewteen SFA intake and CHD deaths or events (280,000 people in 28 studies over 4-25 years)

Major types of dietary fat and risk of coronary heart disease a pooled analysis of 11 cohort studies.  Increased SFA intake not associated with CHD events when replaced with CHO or MUFA (344,698 people from 11 studies over 4-10 years)

Meta-analysis of prospective cohort studies evaluating the association of saturated fat with cardiovascular disease. – No association between SFA intake and CVD, CHD, or stroke (347,747 people from 21 pooled studies 5-23 years)

Dietary Fatty Acids and Risk of Coronary Heart Disease in Men   Our results suggest that SFA intake is not an independent risk factor for CHD, even in a population with higher ranges of SFA intake. In contrast, polyunsaturated fat intake was associated with lower risk of fatal CHD, whether replacing SFA, trans fat, or carbohydrates. Further investigation on the effect of monounsaturated fat on the CHD risk is warranted.

Dairy consumption and risk of cardiovascular disease an updated meta-analysis of prospective cohort studies.   A meta-analysis of prospective epidemiologic studies showed that there is no significant evidence for concluding that dietary saturated fat is associated with an increased risk of CHD or CVD. More data are needed to elucidate whether CVD risks are likely to be influenced by the specific nutrients used to replace saturated fat.



23 Studies on Low-Carb and Low-Fat Diets – Time to Retire The Fad << EXCELLENT LINKS to STUDIES

Low-Carb Diets – Healthy, but Hard to Stick to_

Randomized Controlled Trials in Nutrition

12 Popular Weight Loss Pills and Supplements Reviewed

Sodium Bicarbonate Supplements and Exercise Performance


Low-Carb_Ketogenic Diets and Exercise Performance

Ketogenic Diets and Cancer – A Review of The Research

A Ketogenic Diet to Lose Weight and Fight Disease

The Ketogenic Diet 101_ A Detailed Beginner’s Guide

The Alkaline Diet Myth_ An Evidence-Based Review

Low-Carb vs Vegan and Vegetarian Diets

5 Studies on The Paleo Diet – Does it Actually Work_

10 Graphs That Show the Power of a Ketogenic Diet

10 False Things People Say About Low-Carb Diets

12 Popular Weight Loss Pills and Supplements Reviewed

Randomized Controlled Trials in Nutrition

The Atkins Diet_ Everything You Need to Know (Literally)

7 Healthy Low-Carb Meals in Under 10 Minutes

4 Meal Plans For Diets That Are Supported by Science

What is Ketosis, and is it Healthy_


Fresh meat…How sweet: A Review of the badness of meat

A review of large-scale studies involving more than 1.5 million people found all-cause mortality is higher for those who eat meat, particularly red or processed meat, on a daily basis. Conducted by physicians from Mayo Clinic in Arizona, “Is Meat Killing Us?”  Is Meat Killing Us PDF

The authors analyzed six studies that evaluated the effects of meat and vegetarian diets on mortality with a goal of giving primary care physicians evidence-based guidance. The data found the steepest rise in mortality at the smallest increases of intake of total red meat. That 2014 study followed more than one million people over 5.5 to 28 years and considered the association of processed meat (such as bacon, sausage, salami, hot dogs and ham), as well as unprocessed red meat (including uncured, unsalted beef, pork, lamb or game). Results: Physicians should advise patients to limit animal products when possible and consume more plants than meat.  They also found a 3.6-year increase in life expectancy for those on a vegetarian diet for more than 17 years, as compared to short-term vegetarians. 

Red Meat and Processed Meat Consumption and All-Cause Mortality A Meta-Analysis  <<   In a dose-response meta-analysis, consumption of processed meat and total red meat, but not unprocessed red meat, was statistically significantly positively associated with all-cause mortality in a nonlinear fashion.


Fruit and vegetable consumption and mortality from all causes, cardiovascular disease, and cancer_ systematic review and dose-response meta-analysis of prospective cohort studies  <<-Sixteen prospective cohort studies were eligible in this meta-analysis. During follow-up periods ranging from 4.6 to 26 years there were 56,423 deaths (11,512 from cardiovascular disease and 16,817 from cancer) among 833,234 participants. Higher consumption of fruit and vegetables was significantly associated with a lower risk of all cause mortality.

Carcinogenicity of consumption of red and processed meat << After thoroughly reviewing the accumulated scientific literature, a Working Group of 22 experts from 10 countries, based on limited evidence felt that the consumption of red meat causes cancer in humans and strong mechanistic evidence supporting a carcinogenic effect. Processed meat was classified as carcinogenic to humans (Group 1), based on sufficient evidence in humans that the consumption of processed meat causes colorectal cancer. The experts concluded that each 50 gram portion of processed meat eaten daily increases the risk of colorectal cancer by 18%.

Red meat refers to unprocessed mammalian muscle meat—for example, beef, veal, pork, lamb, mutton, horse, or goat meat—including minced or frozen meat; it is usually consumed cooked. Processed meat refers to meat that has been transformed through salting, curing, fermentation, smoking, or other processes to enhance fl avour or improve preservation. Most processed meats contain pork or beef, but might also contain other red meats, poultry, off al (eg, liver), or meat byproducts such as blood.  Meat processing, such as curing and smoking, can result in formation of carcinogenic chemicals, including N-nitroso-compounds (NOC) and polycyclic aromatic hydrocarbons (PAH). Cooking improves the digestibility and palatability of meat, but can also produce known or suspected carcinogens, including heterocyclic aromatic amines (HAA) and PAH. High-temperature cooking by panfrying, grilling, or barbecuing generally produces the highest amounts of these chemicals. << Factors affecting heterocyclic aromatic content in meat  

The largest body of epidemiological data concerned colorectal cancer. Data on the association of red meat consumption with colorectal cancer were available from 14 cohort studies. < Meat, fish, and colorectal cancer risk_ the European Prospective Investigation into cancer and nutrition < [ Colorectal cancer risk was positively associated with intake of red and processed meat (highest [>160 g/day] versus lowest [<20 g/day] intake, HR = 1.35, 95% CI = 0.96 to 1.88; Ptrend = .03) and inversely associated with intake of fish (>80 g/day versus <10 g/day, HR = 0.69, 95 % CI = 0.54 to 0.88; Ptrend<.001), but was not related to poultry intake] Also Red Meat, Chicken, and Fish Consumption and Risk of Colorectal Cancer <<Conclusion: Consumption of fresh red meat and processed meat seemed to be associated with an increased risk of rectal cancer. Consumption of chicken and fish did not increase risk.

Consuming well done cooked red meat increases the bacterial mutagenicity of human urine. In three intervention studies in human beings, changes in oxidative stress markers (in urine, faeces, or blood) were associated with consumption of red meat or processed meat.1 <<< Calcium and α-tocopherol suppress cured-meat promotion of chemically induced colon carcinogenesis in rats and reduce associated biomarkers in human volunteers.

In a huge study of half a million men and women, researchers have demonstrated an association between processed meat and cardiovascular disease and cancer.  Meat consumption and mortality – results from EPIC <<< Often vegetarians have healthier lifestyles than the general population, they are less likely to smoke, are less fat, and are more likely to be physically active.  This EPIC (European Prospective Investigation into Cancer and Nutrition) study involved ten countries and 23 centres in Europe and almost half a million people. In general a diet high in processed meat was linked to other unhealthy choices. Men and women who ate the most processed meat ate the fewest fruit and vegetables and were more likely to smoke. Men who ate a lot of meat also tended to have a high alcohol consumption. A person’s risk of premature death (increased risk of all cause mortality) increased with the amount of processed meat eaten. This is also true after correcting for confounding variables. It is  estimated that 3% of premature deaths each year could be prevented if people ate less than 20g processed meat per day.


Men who regularly eat moderate amounts of processed red meat such as cold cuts (ham/salami) and sausage may have an increased risk of heart failure incidence and a greater risk of death from heart failure. <<Processed and Unprocessed Red Meat Consumption and Risk of Heart Failure   << — Processed meats are preserved by smoking, curing, salting or adding preservatives. Examples include cold cuts (ham, salami), sausage, bacon and hot dogs. Processed red meat commonly contains sodium, nitrates, phosphates and other food additives, and smoked and grilled meats also contain polycyclic aromatic hydrocarbons, all of which may contribute to the increased heart failure risk,  The Cohort of Swedish Men study — the first to examine the effects of processed red meat separately from unprocessed red meat — included 37,035 men 45-79 years old with no history of heart failure, ischemic heart disease or cancer.  Men who ate the most processed red meat (75 grams per day or more) had a 28 percent higher risk of heart failure compared to men who ate the least (25 grams per day or less) after adjusting for multiple lifestyle variables. Men who ate the most processed red meat had more than a 2-fold increased risk of death from heart failure compared to men in the lowest category. For each 50 gram (e.g. 1-2 slices of ham) increase in daily consumption of processed meat, the risk of heart failure incidence increased by 8 percent and the risk of death from heart failure by 38 percent.

Red Meat Consumption and Mortality << Conclusions:  Red meat consumption is associated with an increased risk of total, CVD, and cancer mortality. Substitution of other healthy protein sources for red meat is associated with a lower mortality risk. We estimated that substitutions of 1 serving per day of other foods (including fish, poultry, nuts, legumes, low-fat dairy, and whole grains) for 1 serving per day of red meat were associated with a 7% to 19% lower mortality risk. We also estimated that 9.3% of deaths in men and 7.6% in women in these cohorts could be prevented at the end of follow-up if all the individuals consumed fewer than 0.5 servings per day (approximately 42 g/d) of red meat.

Vegetarian diets, low-meat diets and health a review  Both vegetarian diets and prudent diets allowing small amounts of red meat are associated with reduced risk of diseases, particularly CHD and type 2 diabetes. There is limited evidence of an association between vegetarian diets and cancer prevention. Evidence linking red meat intake, particularly processed meat, and increased risk of CHD, cancer and type 2 diabetes is convincing and provides indirect support for consumption of a plant-based diet.

Milk Consumption and Mortality from All Causes, Cardiovascular Disease, and Cancer A Systematic Review and Meta-Analysis.  << No observed no consistent association between milk consumption and all-cause or cause-specific mortality. We therefore conducted a systematic review and meta-analysis to evaluate any potential association between non-fermented milk consumption and mortality from all causes, overall cardiovascular disease, and overall cancer.

Food sources of nitrates and nitrites the physiologic context for potential health benefits.   —Approximately 80% of dietary nitrates are derived from vegetable consumption; sources of nitrites include vegetables, fruit, and processed meats. Nitrites are produced endogenously through the oxidation of nitric oxide and through a reduction of nitrate by commensal bacteria in the mouth and gastrointestinal tract. As such, the dietary provision of nitrates and nitrites from vegetables and fruit may contribute to the blood pressure–lowering effects of the Dietary Approaches to Stop Hypertension (DASH) diet. We quantified nitrate and nitrite concentrations by HPLC in a convenience sample of foods. Incorporating these values into 2 hypothetical dietary patterns that emphasize high-nitrate or low-nitrate vegetable and fruit choices based on the DASH diet, we found that nitrate concentrations in these 2 patterns vary from 174 to 1222 mg. The hypothetical high-nitrate DASH diet pattern exceeds the World Health Organization’s Acceptable Daily Intake for nitrate by 550% for a 60-kg adult. These data call into question the rationale for recommendations to limit nitrate and nitrite consumption from plant foods; a comprehensive reevaluation of the health effects of food sources of nitrates and nitrites is appropriate. The strength of the evidence linking the consumption of nitrate- and nitrite-containing plant foods to beneficial health effects supports the consideration of these compounds as nutrients.

Nitrate-containing beetroot enhances myocyte metabolism and mitochondrial content  < The goodness of plants! Cells treated with beetroot exhibited significantly increased oxidative metabolism, concurrently with elevated metabolic gene expression including peroxisome proliferator-activated receptor gamma coactivator-1 alpha, nuclear respiratory factor 1, mitochondrial transcription factor A, and glucose transporter 4, leading to increased mitochondrial biogenesis. Our data show that treatment with a beetroot supplement increases basal oxidative metabolism. Our observations are also among the first to demonstrate that beetroot extract is an inducer of metabolic gene expression and mitochondrial biogenesis. These observations support the need for further investigation into the therapeutic and pharmacological effects of nitrate-containing supplements for health and athletic benefits.






Treatment of human muscle cells with popular dietary supplements increase mitochondrial function and metabolic rate.

Irisin, a unique non-inflammatory myokine in stimulating skeletal muscle metabolism

NO-Rich Diet for Lifestyle-Related Diseases.

Vascular effects of dietary nitrate (as found in green leafy vegetables and beetroot) via the nitrate-nitrite-nitric oxide pathway.

Leucine treatment enhances oxidative capacity through complete carbohydrate oxidation and increased mitochondrial density in skeletal muscle cells

Leucine partially protects muscle mass and function during bed rest in middle-aged adults

PGC-1α-mediated adaptations in skeletal muscle

Mitochondrial Quality Control and Muscle Mass Maintenance.

Mitochondrial pathways in sarcopenia of aging and disuse muscle atrophy.

Sarcopenia – The search for emerging biomarkers

Biomarkers for physical frailty and sarcopenia state of the science and future developments.

Successful aging Advancing the science of physical independence in older adults.

Persistent Inflammation

Effect of beta-hydroxy-beta-methylbutyrate supplementation on muscle loss in elderly adults


A high whey protein–, leucine-, and vitamin D–enriched supplement preserves muscle mass




Whole plant foods and the Microbiome

Abstract Verbatim : Whole plant foods, including fruit, vegetables, and whole grain cereals, protect against chronic human diseases such as heart disease and cancer, with fiber and polyphenols thought to contribute significantly. These bioactive food components interact with the gut microbiota, with gut bacteria modifying polyphenol bioavailability and activity, and with fiber, constituting the main energy source for colonic fermentation. In humans, whole grain cereals can modify fecal bacterial profiles, increasing relative numbers of bifidobacteria and lactobacilli. Polyphenol-rich chocolate and certain fruits have also been shown to increase fecal bifidobacteria. The recent FLAVURS study provides novel information on the impact of high fruit and vegetable diets on the gut microbiota. Increasing whole plant food consumption appears to upregulate beneficial commensal bacteria and may contribute toward the health effects of these foods.

Plant polyphenols are a class of chemically diverse secondary metabolites that possess many different biological activities both within the plant and in the animals which eat these plants. They have long been studied for their interactions with mammalian physiological processes that play a role in chronic human disease. They are antioxidants and possess inherent free radical scavenging abilities. Plant polyphenols have the potential to affect certain risk factors of cardiovascular disease such as plasma lipid oxidation state, endothelial function, and platelet aggregation; protect against cancer by reducing DNA damage, cell proliferation, and metastasis; modulate immune function; inhibit bacterial pathogens; and protect against neurological decline.

Some 1000 species of bacteria  are known to make up the microbiota in the human gut. They play an important role in human health and disease, and interindividual variation in microbiota makeup influences the profile of metabolites released from dietary components that reach the colon and may also affect an individual’s risk of chronic disease.

There are  a limited number of “enterotypes” within the human gut microbiota characterized by a predominance of Prevotella, Bacteroides, and/or Ruminococcus.

Dietary changes in carbohydrates and fats can alter the makeup of one’s microbiota within 24 hours. 6 Different profiles of gut bacteria have also been characterized in populations with chronic immune or metabolic-related diseases including inflammatory bowel disease (IBD), celiac disease, diabetes, and obesity.

Intestinal microbiota in inflammatory bowel disease Friend or foe

Gut microbiota controls adipose tissue expansion, gut barrier and glucose metabolism

Pathophysiological role of host microbiota in the development of obesity.

The Influence of the Gut Microbiome on Obesity, Metabolic Syndrome and Gastrointestinal Disease

Typically, these conditions present with lower prevalence of beneficial butyrate-producing bacteria, such as Faecalibacterium prausnitzii, and the bifidobacteria, which appear to be indicative of a well-functioning, healthy saccharolytic type microbiota. In dysbiotic microbiomes, there is a high prevalence of Enterobacteriaceae, a phylum that includes many important gastrointestinal pathogens including Escherichia coli, Shigella, Salmonella, Campylobacter, and Helicobacter. These diseases too are often associated with increased intestinal permeability or “leaky gut”.

There has been found to be differences in the gut microbiomes of obese and lean individuals:

The obese appear to be typified by a gut microbiota with a reduced Bacteroidetes/Firmicutes ratio and perturbations within important fiber-degrading saccharolytic populations

Obesity and the gut microbiota does up-regulating colonic fermentation protect against obesity and metabolic disease

Microbial ecology Human gut microbes associated with obesity

Rural African children, following a traditional diet rich in whole plant foods, had a microbiota composition strikingly different from that of their European counterparts. Their microbiota was dominated by Bacteroidetes, notably the Prevotella and novel fiber-degrading species such as Xylanibacter, whereas the Italian children had a much lower ratio of Bacteroidetes to Firmicutes. The Italian children also had higher relative abundance of enterobacteria, including E. coli, Shigella, and Salmonella. <<<—Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa  This plant based diet also resulted in a three fold increase in the relative amount of SCFA (short chained fatty acids) in the stool of Afican children. The bottom line is that poor dietary eating patterns, such as less vegetables and fruit intake results in a dysbiotic microbiome and poorer health as found in obesity, inflammatory bowel diseases, and even certain cancers. > The type and quantity of dietary fat and carbohydrate alter faecal microbiome and short-chain fatty acid excretion in a metabolic syndrome ‘at-risk’ population  —Abstract is as follows: An obese-type human microbiota with an increased Firmicutes:Bacteroidetes ratio has been described that may link the gut microbiome with obesity and metabolic syndrome (MetS) development. Dietary fat and carbohydrate are modifiable risk factors that may impact on MetS by altering the human microbiome composition. We determined the effect of the amount and type of dietary fat and carbohydrate on faecal bacteria and short chain fatty acid (SCFA) concentrations in people ‘at risk’ of MetS. : A total of 88 subjects at increased MetS risk were fed a high saturated fat diet (HS) for 4 weeks (baseline), then randomised onto one of the five experimental diets for 24 weeks: HS; high monounsaturated fat (MUFA)/high glycemic index (GI) (HM/HGI); high MUFA/low GI (HM/LGI); high carbohydrate (CHO)/high GI (HC/HGI); and high CHO/low GI (HC/LGI). Dietary intakes, MetS biomarkers, faecal bacteriology and SCFA concentrations were monitored. RESULTS: High MUFA diets did not affect individual bacterial population numbers but reduced total bacteria and plasma total and LDL-cholesterol. The low fat, HC diets increased faecal Bifidobacterium (P ¼ 0.005, for HC/HGI; P ¼ 0.052, for HC/LGI) and reduced fasting glucose and cholesterol compared to baseline. HC/HGI also increased faecal Bacteroides (P ¼ 0.038), whereas HC/LGI and HS increased Faecalibacterium prausnitzii (P ¼ 0.022 for HC/HGI and P ¼ 0.018, for HS). Importantly, changes in faecal Bacteroides numbers correlated inversely with body weight (r ¼ 0.64). A total bacteria reduction was observed for high fat diets HM/HGI and HM/LGI (P ¼ 0.023 and P ¼ 0.005, respectively) and HS increased faecal SCFA concentrations (Po0.01). CONCLUSION: This study provides new evidence from a large-scale dietary intervention study that HC diets, irrespective of GI, can modulate human faecal saccharolytic bacteria, including bacteroides and bifidobacteria. Conversely, high fat diets reduced bacterial numbers, and in the HS diet, increased excretion of SCFA, which may suggest a compensatory mechanism to eliminate excess dietary energy. 

Obese-type gut microbiota, characterised by a higher Firmicutes:Bacteroidetes ratio in obese as opposed to lean, have been observed both in murine models of obesity and humans. Moreover, germ-free mice colonised with the microbiota from obese mice display increased body fat, higher faecal total energy content (by bomb calorimetry) and higher concentrations of faecal short chain fatty acids (SCFA) compared with their conventionally fed lean counterparts, indicating that the microbiota of obese animals may have an increased capacity to harvest energy.15 In addition, weight loss in humans induced by CHOor fat-restricted diets has been associated with a change in gut microbial composition, resembling the microbiota of lean individuals (that is, increased Bacteroidetes). Data from human studies show higher faecal SCFA concentrations in overweight and obese humans compared with their lean counterparts on a similar Western-style diet. Dietary supplementation studies with the prebiotics inulin or oligofructose in humans and animals have shown that changes in colonic SCFA are accompanied by reduced plasma lipids, particularly in those with hyperlipidaemia and hypercholesterolaemia.

For example in :Balca´zar-Mun˜oz BR, Mart´ınez-Abundis E, Gonza´lez-Ortiz M. Effect of oral inulin administration on lipid profile and insulin sensitivity in subjects with obesity and dyslipidemia. Rev Med Chil 2003; 131: 597 — 604: Abstract as follows:

BACKGROUND: Inulin is a non absorbable polysaccharide with prebiotic effects, whose influence on blood lipidsor insulin sensitivity is not well known: AIM: To assess the effect of oral administration of inulin on lipid profile and insulin sensitivity in dyslipidemic obese subjects. MATERIAL AND METHODS: A clinical trial, double blind, randomized with placebo was carried out in 12 obese, hypertrygliceridemic and hypercholesterolemic subjects between 19 and 32 years old. The subjects were randomized to receive 7 g/day of inulin or placebo in the morning, during 4 weeks. Biochemical and metabolic profiles and euglycemic-hyperinsulinemic clamp technique for assessing insulin sensitivity, before and after pharmacological intervention were performed.

RESULTS: After inulin administration, there was a significant reduction of total cholesterol (248.7 +/- 30.5 and 194.3 +/- 39.8 mg/dL; p = 0.028), low density lipoprotein (LDL), cholesterol (136.0 +/- 27.8 and 113.0 +/- 36.2 mg/dL; p = 0.028), very low density lipoproteins (VLDL) (45.9 +/- 18.5 and 31.6 +/- 7.2 mg/dL; p = 0.046) and trygliceride concentrations (235.5 +/- 85.9 and 171.1 +/- 37.9 mg/dL; p = 0.046). No effect of inulin on insulinsensitivity was observed.

CONCLUSIONS: The oral inulin administration reduced total cholesterol, LDL cholesterol, VLDL and trygliceride levels in dyslipidemic and obese subjects, without modifications in the insulin sensitivity.

The effect of the daily intake of inulin on fasting lipid, insulin and glucose concentrations in middle-aged men and women


The intestinal microbiome and health.

A healthy gastrointestinal microbiome is dependent on dietary diversity.


The most recent definition of a prebiotic defines a dietary prebiotic as “… a selectively fermented ingredient that results in specific changes, in the composition and/or activity of the gastrointestinal microbiota, thus conferring benefit(s) upon host health”. There is also strong animal data linking prebiotics with protection from metabolic syndrome, obesity, type 2 diabetes, colon cancer, and IBD and fortifying the gut microbiota against invading gastrointestinal pathogens. < Prebiotic effects metabolic and health benefits.

Probiotics and Prebiotics Present Status and Future Perspectives on Metabolic Disorders

Plant complex polysacharides are fiber and we consume 20 g/day on average wheras our ancestors consumed 70-120 g/day. Starch is resistant to degradation and reaches the colon unaltered. Food processin g and preparation can affect the amount of dietary starch becoming resistant as well, and likewise, polyphenol-ruch beverages blunt the post-prandial rise of glucose by altering starch digestion. Once these food compounds reach the colon, they become available to the fermentative activities of the human colonic microbiota. Gut microbiota is specifically evolved for the digestion of complex plant polysaccharides, possessing a range of polysaccharide- and glycan-degrading enzymes not present in the human genome  <<- Metagenomic analysis of the human distal gut microbiome  Thus the gut microbiota has coevolved with us to extract energy from foods we could not otherwise digest ourselves.

The dominant fermentative activity is carbohydrate fermentation leading to the production of the short-chain fatty acids acetate, propionate, and butyrate. They play a role in supplying energy to the heart, brain,muscle and intestinal mucosa and also play mportant roles in human cell differentiation, proliferation, and programmed cell death; regulation of immune function; thermogenesis; and lipid metabolism.

Asdietary fiber and carbohydrates are used up along the colon, the bacteria can switch to using other sources of energy such as proteins and amino acids. The end products of amino acid fermentation include SCFA but also branched-chain fatty acids, amines, indoles, sulfides, and phenols, some of which are potentially harmful, being variably genotoxic, cytotoxic, and carcinogenic.

The more dietary fiber and plant-sources of foods, the higher the SCFA content in the colon. With higher intake of fiber, the bacteria are extended further along the colon before they have to switch to protein/amino acid fermentation. A 3-fold increase in dietary fiber results in a proportional increase in SCFA production by the gut microbiota and extends saccharolytic fermentation into the transverse and distal colon.

Role of the Gut Microbiome in Uremia A Potential therapeutic target

Hydrolysis by the gut microbiota can increase the bioavailability  of polyphenols and the microbiota also breaks down many complex polyphenols into smaller phenolic acids, which can be absorbed and function in humans. Functions ascribed include to phenolic acid catabolites  include antibacterial activities especially against Gram negative species, like the Enterobacteriaea, anti-inflammatory activities, anti-AGE formation, stimulation of xenobiotic degrading enzymes and detoxification processes, and phytoestrogenic activities.

Microbial metabolites of quercetin and chlorogenic acid/caffeic acid, 3,4-dihydroxyphenylacetic acid (ES), and 3-(3,4- dihydroxyphenyl)propionic acid (PS), respectively, could significantly up-regulate GSTT2 expression and decrease COX-2 expression, a modulation seen as protective against colon cancer << — Miene, C.; Weise, A.; Glei, M. Impact of polyphenol metabolites produced by colonic microbiota on expression of COX-2 and GSTT2 in human colon cells (LT97). Nutr. Cancer 2011, 63, 653−662

The microbiome and its potential as a cancer preventive intervention

Gut microbiome and metabolic diseases

Ellagic acid (EA) and its colonic metabolites, urolithin-A (3,8-dihydroxy-6H-dibenzo[b,d]pyran-6-one, Uro-A) and urolithin-B (3-hydroxy-6H-dibenzo[b,d]pyran-6-one, Uro-B), modulate the expression and activity of CYP1A1 and UGT1A10 and inhibit several sulfotransferases in colon cancer cell lines (Caco-2). These phase I and phase II detoxifying enzymes are important components of how our bodies deal with toxic and xenobiotic compounds, and increased expression is associated with a reduced risk of colon cancer in laboratory animals  << Gonzalez-Sarr ́ ıas, A.; Azorín-Ortun ́ ̃ o, M.; Yań ̃ ez-Gascon, M. J.; ́ Tomas-Barbera ́ n, F. A.; Garc ́ ıa-Conesa, M. T.; Esp ́ ın, J. C. Dissimilar ́ in vitro and in vivo effects of ellagic acid and its microbiota-derived metabolites, urolithins, on the cytochrome P450 1A1. J. Agric. Food Chem. 2009, 57, 5623−5632

Urolithins, from pomegranate, had, however, already been shown to reduce the growth of cancer cells in an animal model of prostate cancer << Seeram, N. P.; Aronson, W. J.; Zhang, Y.; Henning, S. M.; Moro, A.; Lee, R. P.; Sartippour, M.; Harris, D. M.; Rettig, M.; Suchard, M. A.; Pantuck, A. J.; Belldegrun, A.; Heber, D. Pomegranate ellagitanninderived metabolites inhibit prostate cancer growth and localize to the mouse prostate gland. J. Agric. Food Chem. 2007, 55, 7732−7737

Microbial catabolites might, at least in part, account for the observed anti-inflammatory activity of certain herbal medicines and functional foods: ferulaldehyde, a microbial catabolite of curcumin, has anti-inflammatory properties in vivo in an animal model of LSP-induced septic shock : Ferulaldehyde, a Water-Soluble Degradation Product of Polyphenols, Inhibits the Lipopolysaccharide-Induced Inflammatory Response in Mice

Modulatory Effects of Gut Microbiota on the Central Nervous System How Gut Could Play a Role in Neuropsychiatric Health and Diseases

Gut Microbiota The Brain Peacekeeper.

Role of Resistant Starch in Improving Gut Health, adiposity and insulin resistance

Resistant starch and protein intake enhances fat oxidation and feelings of fullness in lean and overweight obese women.

Modulation of Gut Microbiota−Brain Axis by Probiotics, Prebiotics, and diet

‘The way to a man’s heart is through his gut microbiota’ – dietary pro- and prebiotics for the management of cardiovascular risk

The 3,4-dihydroxyphenylpropionic acid (3,4-DHPPA), 3- hydroxyphenylpropionic acid, and 3,4-dihydroxyphenylacetic acid (3,4-DHPAA), derived from colonic catabolism of proanthocyanidins, have been shown to reduce the inflammatory response of human peripheral blood mononuclear cells stimulated with lipopolysaccharide (LPS), an inflammatory cell wall component from Gram-negative bacteria such as the Enterobacteriaceae. Secretion of IL-6, IL-1, and TNF-α was reduced, suggesting that microbial metabolites may be involved in dampening the inflammatory response to bacterial antigens.  <<– Dihydroxylated phenolic acids derived from microbial metabolism reduce lipopolysaccharide-stimulated cytokine secretion by human peripheral blood mononuclear cells

Chlorogenic acid-microbially derived catabolites, dihydrocaffeic acid, dihydroferulic acid, and feruloylglycine, were most effective at protecting cultured neural cells in vitro, indicating that colonic catabolites of dietary polyphenols may play an important role in the improved cognitive function and protection from neuronal degeneration observed in animals fed polyphenol-rich foods such as certain berries.

Urolithins and pyrogallol, microbial ellagitannin-derived catabolites, are highly antiglycative compared to parent polyphenolic compounds in an in vitro model of protein glycation.<<– Antiglycative and neuroprotective activity of colon-derived polyphenol catabolites


Interaction of dietary compounds, especially polyphenols, with the intestinal microbiota a review

Gut Microbiota, Intestinal Permeability, Obesity-Induced Inflammation, and Liver Injury

Flos Lonicera ameliorates obesity and associated endotoxemia in rats through modulation of gut permeability and intestinal microbiota.

Metabolic endotoxaemia is it more than just a gut feeling

Fermented Rhizoma Atractylodis Macrocephalae alleviates high fat diet-induced obesity in association with regulation of intestinal permeability and microbiota in rats

Probiotics- Interaction with gut microbiome and antiobesity potential

Maturation of Oral Microbiota in Children with or without Dental Caries.

Role of the microbiome in energy regulation and metabolism.

Role of Intestinal Microbiome in Lipid and Glucose Metabolism in Diabetes Mellitus

Getting Personal About Nutrition

More than just a gut instinct-the potential interplay between a baby’s nutrition, its gut microbiome, and the epigenome.

Individuals on a Western style, low-fiber diet, the proximal colon is the major site of saccharolytic fermentation, with potentially damaging proteolytic fermentation increasing distally as carbohydrate substrate becomes limiting. Retardation of carbohydrate fermentation in the proximal colon may extend SCFA production to the distal colon, thereby reducing the harmful effects of amino acid catabolites <<–apple proanthocyanidins inhibited both metabolic degradation of short proanthocyanidins and SCFA production : Factors affecting the conversion of apple polyphenols to phenolic acids and fruit matrix to short-chain fatty acids by human faecal microbiota in vitro

Diet Effects in Gut Microbiome and Obesity

The art of targeting gut microbiota for tackling human obesity.

Towards microbial fermentation metabolites as markers for health benefits of prebiotics

Polyphenols have been shown to directly affect the relative abundance of different bacteria within the gut microbiota with tea polyphenols and their derivatives reducing numbers of potential pathogens including Clostridium perfringens and C. difficile and certain Gram-negative Bacteroides spp., with less inhibition toward beneficial clostridia, bifidobacteria, and lactobacilli.

Prebiotic evaluation of cocoa-derived flavanols in healthy humans by using a randomized, controlled, double-blind, crossover intervention study <<–  Abstract:

Twenty-two healthy human volunteers were randomly assigned to either a high-cocoa flavanol (HCF) group (494 mg cocoa flavanols/d) or a low-cocoa flavanol (LCF) group (23 mg cocoa flavanols/d) for 4 wk. This was followed by a 4-wk washout period before volunteers crossed to the alternant arm. Fecal samples were recovered before and after each intervention, and bacterial numbers were measured by fluorescence in situ hybridization. A number of other biochemical and physiologic markers were measured.


Compared with the consumption of the LCF drink, the daily consumption of the HCF drink for 4 wk significantly increased the bifidobacterial (P < 0.01) and lactobacilli (P < 0.001) populations but significantly decreased clostridia counts (P < 0.001). These microbial changes were paralleled by significant reductions in plasma triacylglycerol (P < 0.05) and C-reactive protein (P < 0.05) concentrations. Furthermore, changes in C-reactive protein concentrations were linked to changes in lactobacilli counts (P < 0.05, R(2) = -0.33 for the model). These in vivo changes were closely paralleled by cocoa flavanol-induced bacterial changes in mixed-batch culture experiments.


This study shows, for the first time to our knowledge, that consumption of cocoa flavanols can significantly affect the growth of select gut microflora in humans, which suggests the potential prebiotic benefits associated with the dietary inclusion of flavanol-rich foods. 

Effects of cocoa flavanols on risk factors for cardiovascular risk

Diet, gut microbiome, and bone health.

Whole grain breakfast cereals have been shown to mediate a prebiotic modulation of the gut microbiota, giving significant increases in fecal bifidobacteria and/or lactobacilli without changing the relative abundance of other dominant members of the gut microbiota. Also, Ingestion of either whole grain wheat or wheat bran breakfast cereal increased plasma and urine concentrations of ferulic acid, a polyphenol commonly complexed with dietary fiber in whole grain cereals. << Whole-grain wheat breakfast cereal has a prebiotic effect on the human gut microbiota a double-blind, placebo-controlled, crossover study


In the FLAVURS group study, they investigated the relative impact of increased fruit and vegetable intake of differing flavonoid content on markers of cardiovascular disease risk. BAsic scheme was: A  habitual diet, a high-flavonoid fruit and vegetable diet, or a low-flavonoid fruit and vegetable diet for 18 weeks were compared for health effects. —> Independent analysis of fecal bacteria revealed that in the first cohort (n = 59), dietary intervention with either flavonoid-rich or flavonoid-poor fruits and vegetables significantly increased groups of commensal bacteria important for human health including Bifidobacterium, Atopobium, Ruminococcus, Roseburia, Eubacterium, and Faecalibacterium prausnitzii, whereas the flavonoid-poor diet also increased lactobacilli compared to the control diet.

Chong, M. F.; Geroge, T. W.; Alimbetov, D.; Jin, Y.; Weech, M.; Spencer, J. P. E.; Kennedy, O. B.; Minihane, A.-M.; Gordon, M. H.; Lovegrove, J. A. (For the FLAVURS group) Impact of the quantity and flavonoid content of fruits and vegetables on markers of intake in adults with an increate risk of cardiovascular disease: the FLAVURS Trial. Eur. J. Nutr. 2012, DOI: 10.1007/s00394-012-0343-3.: Abstract below:


Limited robust randomised controlled trials investigating fruit and vegetable (F&V) intake in people at risk of cardiovascular disease (CVD) exist. We aimed to design and validate a dietary strategy of increasing flavonoid-rich versus flavonoid-poor F&V consumption on nutrient biomarker profile.


A parallel, randomised, controlled, dose–response dietary intervention study. Participants with a CVD relative risk of 1.5 assessed by risk scores were randomly assigned to one of the 3 groups: habitual (control, CT), high-flavonoid (HF) or low-flavonoid (LF) diets. While the CT group (n = 57) consumed their habitual diet throughout, the HF (n = 58) and LF (n = 59) groups sequentially increased their daily F&V intake by an additional 2, 4 and 6 portions for 6-week periods during the 18-week study.


Compliance to target numbers and types of F&V was broadly met and verified by dietary records, and plasma and urinary biomarkers. Mean (±SEM) number of F&V portions/day consumed by the HF and LF groups at baseline (3.8 ± 0.3 and 3.4 ± 0.3), 6 weeks (6.3 ± 0.4 and 5.8 ± 0.3), 12 weeks (7.0 ± 0.3 and 6.8 ± 0.3) and 18 weeks (7.6 ± 0.4 and 8.1 ± 0.4), respectively, was similar at baseline yet higher than the CT group (3.9 ± 0.3, 4.3 ± 0.3, 4.6 ± 0.4, 4.5 ± 0.3) (P = 0.015). There was a dose-dependent increase in dietary and urinary flavonoids in the HF group, with no change in other groups (P = 0.0001). Significantly higher dietary intakes of folate (P = 0.035), non-starch polysaccharides (P = 0.001), vitamin C (P = 0.0001) and carotenoids (P = 0.0001) were observed in both intervention groups compared with CT, which were broadly supported by nutrient biomarker analysis.


The success of improving nutrient profile by active encouragement of F&V intake in an intervention study implies the need for a more hands-on public health approach.

Fatty acids from diet and microbiota regulate energy metabolism.


High-fat diet reduces the formation of butyrate, but increases succinate, inflammation, liver fat and cholesterol in rats, while dietary fibre counteracts these effects.

Review article dietary fibre-microbiota interactions.

Obesity Reduces Cognitive and Motor Functions across the Lifespan.




Review of natural products actions on cytokines in inflammatory bowel disease

The strawberry Composition, nutritional quality, and impact on human health

Ellagic acid, pomegranate and prostate cancer — a mini review



Basis of above is as follows: Up-regulating the Human Intestinal Microbiome Using Whole Plant food and polyphenols and fibers








Life extension – healthspan – strategies for successful aging

Dietary restriction with and without caloric restriction for healthy aging

“Caloric restriction is the most effective and reproducible dietary intervention known to regulate aging and increase the healthy lifespan in various model organisms, ranging from the unicellular yeast to worms, flies, rodents, and primates.  However, caloric restriction, which in most cases entails a 20–40% reduction of food consumption relative to normal intake, is a severe intervention that results in both beneficial and detrimental effects. Specific types of chronic, intermittent, or periodic dietary restrictions without chronic caloric restriction have instead the potential to provide a significant healthspan increase while minimizing adverse effects.”

CAloric restriction (CR)  refers to a dietary intervention with an overall 20–40% reduction of total caloric intake, and dietary restriction to represent a broader scope of dietary interventions that encompass those with specific macronutrient and feeding pattern restrictions. There is mounting evidence that healthspan can be maximized and aging  can be reduced by  methods other than caloric reduction.

In 1935, Crowell and McCay demonstrated that simply reducing caloric intake without causing malnutrition nearly doubled the lifespan of rats.

Walford and Weindruch reported that “adult-initiated” caloric restriction started at 12 months of age not only increased lifespan but also reduced the incidence of spontaneous cancer by more than 50% in rats. Dietary Restriction in Mice Beginning at 1 Year of Age effect on life span and cancer  This same effect has been shown in yeast, worms, flies, and other animals, hence the genes for this are highly conserved.  Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys

Caloric restriction and lifespan extension involves the down-regulation of insulin and insulin-like signalling (IIS)[ The genetics of ageing ], as well as of the amino signalling target of rapamycin (TOR)-S6 kinase pathway [Regulation of Lifespan in Drosophila by Modulation of Genes in the TOR Signaling Pathway and Regulation of Longevity and Stress Resistance by Sch9 in Yeast , and the glucose signalling Ras-protein kinase A (PKA) pathway[The Ras-Erk-ETS-Signaling Pathway Is a Drug Target for longevity]

In yeast, down-regulation of (a) the amino acid-sensing TOR and the ribosomal protein S6 kinase (S6K) ortholog Sch9 pathway6 , and (b) the Ras-AC-PKA pathway13 [Life Span Extension by Calorie Restriction Depends on Rim15 and Transcription Factors Downstream of Ras PKA, Tor, and Sch9 ] are key changes mediating part of the effects of caloric restriction on chronological lifespan, the measurement of cellular survival under non-dividing conditions. In contrast, elevated activity of sirtuin (SIR2) [ Sir2 Blocks Extreme Life-Span Extension] and [Requirement of NAD and SIR2 for Life-Span Extension by Calorie Restriction in Saccharomyces cerevisiae  has been described as a key change in the extension of replicative lifespan, measured by counting the number of buds generated by an individual mother cell In worms, the lifespan extension caused by the inactivation of IIS, or by different forms of caloric restriction, requires Forkhead FoxO transcription factor daf-16 Different dietary restriction regimens extend lifespan by both independent and overlapping genetic pathways in C. elegans  . In rodents, growth hormone (GH) and IGF-1 levels are reduced following caloric restriction Fasting vs dietary restriction in cellular protection and cancer treatment from model organisms to patients, but the link between dietary restriction, GH and aging is still being investigated, with focus on the genes and pathways regulating longevity in the simple organisms described above.

The ultimate question that lingers is the relevance of these models to human lifespan and healthspan.  Two notable studies performed by independent programs, the National Institute on Aging (NIA) Intramural Research Program and the Wisconsin National Primate Research Center (WNPRC), subjected male and female rhesus monkeys to 30% caloric restriction from levels of baseline caloric intake. The NIA reported no improvement in lifespan but observed a positive trend for the delay of age-related diseases (i.e. healthspan) Impact of caloric restriction on health and survival in rhesus monkes – the NIA study, whereas WNPRC reported significant improvement in both lifespan and healthspan Caloric restriction delays disease onset and mortality in rhesus monkeys

CALERIE (Comprehensive Assessment of the Long term Effects of Reducing Intake of Energy), recently reported that a two year 25% caloric restriction is feasible for humans and provides health benefits, such as reduced inflammatory markers and cardiometabolic risk factors. A 2-Year Randomized Controlled Trial of Human Caloric Restriction Feasibility and Effects on Predictors of Health Span and Longevity  and Energy requirements in nonobese men and women results from CALERIE and Caloric Restriction in Humans

CALERIE was conducted in three independent centers and involved 218 overweight participants, suggesting that caloric restriction can be beneficial even in a very genetically heterogeneous group. Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy Phase 2 (CALERIE Phase 2) Screening and Recruitment Methods and Results

The ability of caloric restriction to prevent the damage caused by exogenous toxins is likely to be associated with the protection, repair and replacement effects that prevent the age-dependent dysfunction caused by endogenous processes and toxic molecules. CALORIE RESTRICTION AND AGING A LIFE-HISTORY ANALYSIS At the cellular level, caloric restriction and longevity mutations allow resistance to stressors, especially oxidative stress.

Likewise, it could be that hormesis occurs, in which repeat stresses allow adaptation and survival.

Dietary options for food restriction include: short-term starvation, periodic fasting, fasting-mimetic diets, intermittent fasting, normocaloric diets with planned deficiencies (in particular macronutrients: proteins, carbohydrates, etc.), and time-restricted feeding.Fasting involves a 60% decrease in food intake. Intermittent fasting refers to practicing this intervention every other day whereas periodic fasting refers to severe restriction for two or more days periodically (every two weeks, month, etc.) Caloric restriction and fasting result in lower glucose levels and insulin levels. Fasting vs dietary restriction in cellular protection and cancer treatment from model organisms to patients  Both intermittent and periodic fasting can increase lifespan, even when there is little or no overall decrease in calorie intake. Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from calorie intake and Brandhorst S, Choi IY, Wei M, et al.: A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan. Cell Metab. 2015; 22(1): 86–99. 

The restriction of specific macronutrients (or macronutrient restriction) without the restriction of calories is among the most promising interventions that have emerged to promote healthy aging in humans, with  reduced intake of proteins and amino acids is the most effective pro-longevity intervention: Protein and amino acid restriction, aging and disease from yeast to humans [ Protein or Anino Acid (AA)  restriction has been shown to be as potent as calorie restriction in extending healthspan in multiple model organisms. AA restriction affects lifespan partly through modulation of the amino acid sensing pathways TOR and GCN2. Human epidemiological studies highlight the detrimental effects of high protein diets, in particular animal-derived protein sources in contrast to plant-based sources. Epidemiological studies indicate that low protein diets are associated with lower risk of chronic and age-related diseases such as CVDs, diabetes, and cancer.]  Also, Amino acid imbalance explains extension of lifespan by dietary restriction in Drosophila : Adding essential amino acids to a DR diet increased fecundity and decreased lifespan, similar to full feeding, with other nutrients having little or no effect. However, methionine alone increased fecundity as much as full feeding, but without reducing lifespan. Reallocation of nutrients therefore does not explain the DR responses. Lifespan was reduced by amino acids, particularly essential amino acids. Hence an imbalance in dietary amino acids away from the ratio optimal for reproduction shortens lifespan during full feeding and limits fecundity during DR. Reduced activity of the insulin/Igf signaling pathway extends lifespan in diverse organisms 7, and it protected against the shortening of lifespan with full feeding. In other organisms, including mammals, it may be possible to obtain the benefits for lifespan of DR without reduced fecundity, through a suitable balance of nutrients in the diet.

A recent analysis of the National Health and Nutrition Examination Survey (NHANES) showed that low protein intake was associated with reduced overall mortality for those under 65 years of age. Low Protein Intake Is Associated with a Major Reduction in IGF-1, Cancer, and Overall Mortality in the 65 and Younger but Not Older Population : High protein intake is linked to increased cancer, diabetes, and overall mortality. High IGF-1 levels increased the relationship between mortality and high protein. Higher protein consumption may be protective for older adults. Plant-derived proteins are associated with lower mortality than animal-derived proteins. These results suggest that low protein intake during middle age followed by moderate to high protein consumption in old adults may optimize healthspan and longevity.

A high-carbohydrate, low-protein diet resulted in longer lifespan and improved cardiometabolic health, despite increased food intake and body fat: The Ratio of Macronutrients, Not Caloric Intake, Dictates Cardiometabolic Health, Aging, and Longevity in Ad Libitum-Fed Mice —  Food intake is regulated primarily by dietary protein and carbohydrate. Low-protein, high-carbohydrate diets are associated with the longest lifespans. Energy reduction from high-protein diets or dietary dilution does not extend life. Diet influences hepatic mTOR via branched-chain amino acids and glucose. Longevity and health were optimized when protein was replaced with carbohydrate to limit compensatory feeding for protein and suppress protein intake.Calorie restriction achieved by high-protein diets or dietary dilution had no beneficial effects on lifespan. 

Also: Dietary Protein to Carbohydrate Ratio and Caloric Restriction Comparing Metabolic Outcomes in Mice Abstract: Both caloric restriction (CR) and low-protein, high-carbohydrate (LPHC) ad-libitum-fed diets increase lifespan and improve metabolic parameters such as insulin, glucose, and blood lipids. Severe CR, however, is unsustainable for most people; therefore, it is important to determine whether manipulating macronutrient ratios in ad-libitum-fed conditions can generate similar health outcomes. We present the results of a short-term (8 week) dietary manipulation on metabolic outcomes in mice. We compared three diets varying in protein to carbohydrate ratio under both CR and ad libitum conditions. Ad libitum LPHC diets delivered similar benefits to CR in terms of levels of insulin, glucose, lipids, and HOMA, despite increased energy intake. CR on LPHC diets did not provide additional benefits relative to ad libitum LPHC. We show that LPHC diets under ad-libitum-fed conditions generate the metabolic benefits of CR without a 40% reduction in total caloric intake Ad libitum low-protein, high-carbohydrate diets (LPHC) improve metabolic health. Caloric restriction combined with LPHC diet does not provide added health benefits. Energy intake and energy expenditure are increased on LPHC diets.

The restriction of a single essential amino acid in a normal diet increased lifespan and stress resistance: Zimmerman JA, Malloy V, Krajcik R, et al.: Nutritional control of aging. Exp Gerontol. 2003; 38(1–2): 47–52.  In this paper, reducing specific essential amino acids in rats demonstrated longevity effects. Reduced tryptophan content in the diet extended maximum lifespan. In fact, decreasing sulfhydryl-containing amino acids in the diet by removing cysteine and methionine extended survival. Calorie restriction (CR) delays cancer, reduces the diminution of the immune system in aging, and improves insulin sensitivity.  Essential amino acid restriction in this study, i.e. methionine restriction (MR) , resulted in decreased growth in rats, but produced life extension in the same was as CR would. MR produced 42% increase in longevity. The animals grew less, but they lived longer. As for tryptophan- restricted mice who were fed ad libitum, they too had less growth but lived 10% longer. CR, on the other hand, results in a 65% life extension, but off course the animals had to eat much less. It is felt that oxidation results in age-related physiological defects and that CR attenuates the generation of oxidative end products in aged animals. Glutathions (GSH) is one of the anti-oxidants and detoxifying agents that decreases in aging. This study demonstrated that cysteine-restriction did not decrease levels of GSH, but rather increased GSH levels in mice. Considering that cyteine is a precursor of GSh, this is counter intuitive.

The Abstract:  For more than 60 years the only dietary manipulation known to retard aging was caloric restriction, in which a variety of species respond to a reduction in energy intake by demonstrating extended median and maximum life span. More recently, two alternative dietary manipulations have been reported to also extend survival in rodents. Reducing the tryptophan content of the diet extends maximum life span, while lowering the content of sulfhydryl-containing amino acids in the diet by removing cysteine and restricting the concentration of methionine has been shown to extend all parameters of survival, and to maintain blood levels of the important anti-oxidant glutathione. To control for the possible reduction in energy intake in methionine-restricted rats, animals were offered the control diet in the quantity consumed by rats fed the low methionine diet. Such pair-fed animals experienced life span extension, indicating that methionine restriction-related life span extension is not a consequence of reduced energy intake. By feeding the methionine restricted diet to a variety of rat strains we determined that lowered methionine in the diet prolonged life in strains that have differing pathological profiles in aging, indicating that this intervention acts by altering the rate of aging, not by correcting some single defect in a single strain.

Also: Methionine restriction increases blood glutathione and longevity in F344 rats

Low-protein, high-carbohydrate diet increases glucose uptake and fatty acid synthesis in brown adipose tissue of rats.

De Marte ML, Enesco HE: Influence of low tryptophan diet on survival and organ growth in mice. Mech Ageing Dev. 1986; 36(2): 161–71. Abstract: Greater survival and reduced growth were found to characterize mice on a tryptophan deficient diet as compared to fully fed control mice. The 50% survival point was reached by the tryptophan restricted group at 683 days, and by the control group at 616 days. Measurements of body weight, organ weight, and DNA level were made at 8, 12, 24, 36, 52 and 78 weeks of age. Both whole body weight and organ weight of liver, kidney, heart and spleen were about 30% lower in the tryptophan restricted group as compared to the controls, so that the ratio of organ weight to body weight remained at a constant value for both groups. There was no significant change in cell number as determined by DNA measurements, as a result of the tryptophan restriction.

Ooka H, Segall PE, Timiras PS: Histology and survival in age-delayed low-tryptophan-fed rats. Mech Ageing Dev. 1988; 43(1): 79–98. Abstract:  Diets containing tryptophan in concentrations 30 and 40 percent of those fed to controls from weaning to 24-30 months or more, can delay aging in Long-Evans female rats. Mortality among low-tryptophan-fed rats was greater in the juvenile period, but substantially less than controls at late ages. Histological biomarkers of aging were also delayed after tryptophan restriction in some organs (liver, heart, uterus, ovary, adrenal and spleen) but not in others (kidney, lung, aorta). Brain serotonin levels were low in tryptophan-deficient rats but showed remarkable capacity for rehabilitation. Effects on early and late mortality and brain levels of serotonin were proportional to the severity of the restriction.

Laboratory rodents fed a methionine-restricted diet displayed an extended lifespan with decreased age-dependent diseases and increased resistance to oxidative stress, in part due to increased antioxidant capacity : Methionine restriction increases blood glutathione and longevity in F344 rats. Abstract as follows: Little is known about the biochemical mechanisms responsible for the biological aging process. Our previous results and those of others suggest that one possible mechanism is based on the loss of glutathione (GSH), a multifunctional tripeptide present in high concentrations in nearly all living cells. The recent finding that life-long dietary restriction of the GSH precursor methionine (Met) resulted in increased longevity in rats led us to hypothesize that adaptive changes in Met and GSH metabolism had occurred, leading to enhanced GSH status. To test this, blood and tissue GSH levels were measured at different ages throughout the life span in F344 rats on control or Met-restricted diets. Met restriction resulted in a 42% increase in mean and 44% increase in maximum life span, and in 43% lower body weight compared to controls (P < 0.001). Increases in blood GSH levels of 81% and 164% were observed in mature and old Met-restricted animals, respectively (P < 0.001). Liver was apparently the source for this increase as hepatic GSH levels decreased to 40% of controls. Except for a 25% decrease in kidney, GSH was unchanged in other tissues. All changes in GSH occurred as early as 2 months after the start of the diet. Altogether, these results suggest that dramatic adaptations in sulfur amino acid metabolism occur as a result of chronic Met restriction, leading to increases in blood GSH levels and conservation of tissue GSH during aging.

Methionine-deficient diet extends mouse lifespan, slows immune and lens aging, alters glucose, T4, IGF-I and insulin levels, and increases hepatocyte MIF levels and stress resistance  : A diet deficient in the amino acid methionine has previously been shown to extend lifespan in several stocks of inbred rats. We report here that a methionine-deficient (Meth-R) diet also increases maximal lifespan in (BALB/ cJ × C57BL/6 J)F1 mice. Compared with controls, Meth-R mice have significantly lower levels of serum IGF-I, insulin, glucose and thyroid hormone. Meth-R mice also have higher levels of liver mRNA for MIF (macrophage migration inhibition factor), known to be higher in several other mouse models of extended longevity. Meth-R mice are significantly slower to develop lens turbidity and to show age-related changes in T-cell subsets. They are also dramatically more resistant to oxidative liver cell injury induced by injection of toxic doses of acetaminophen. The spectrum of terminal illnesses in the Meth-R group is similar to that seen in control mice. Studies of the cellular and molecular biology of methionine-deprived mice may, in parallel to studies of calorie-restricted mice, provide insights into the way in which nutritional factors modulate longevity and late-life illnesses.

Life-Span Extension in Mice by Preweaning Food Restriction and by Methionine Restriction in Middle Age  Abstract:   Life span can be extended in rodents by restricting food availability (caloric restriction [CR]) or by providing food low in methionine (Meth-R). Here, we show that a period of food restriction limited to the fi rst 20 days of life, via a 50% enlargement of litter size, shows extended median and maximal life span relative to mice from normal sized litters and that a Meth-R diet initiated at 12 months of age also signifi cantly increases longevity. Furthermore, mice exposed to a CR diet show changes in liver messenger RNA patterns, in phosphorylation of Erk, Jnk2, and p38 kinases, and in phosphorylation of mammalian target of rapamycin and its substrate 4EBP1, HE-binding protein 1 that are not observed in liver from agematched Meth-R mice. These results introduce new protocols that can increase maximal life span and suggest that the spectrum of metabolic changes induced by low-calorie and low-methionine diets may differ in instructive ways.

Methionine restriction decreases visceral fat mass and preserves insulin action in aging male Fischer 344 rats independent of energy restriction Abstract: Reduced dietary methionine intake (0.17% methionine, MR) and calorie restriction (CR) prolong lifespan in male Fischer 344 rats. Although the mechanisms are unclear, both regimens feature lower body weight and reductions in adiposity. Reduced fat deposition in CR is linked to preservation of insulin responsiveness in older animals. These studies examine the relationship between insulin responsiveness and visceral fat in MR and test whether, despite lower food intake observed in MR animals, decreased visceral fat accretion and preservation of insulin sensitivity is not secondary to CR. Accordingly, rats pair fed (pf) control diet (0.86% methinone, CF) to match the food intake of MR for 80 weeks exhibit insulin, glucose, and leptin levels similar to control-fed animals and comparable amounts of visceral fat. Conversely, MR rats show significantly reduced visceral fat compared to CF and PF with concomitant decreases in basal insulin, glucose, and leptin, and increased adiponectin and triiodothyronine. Daily energy expenditure in MR animals significantly exceeds that of both PF and CF. In a separate cohort, insulin responses of older MR animals as measured by oral glucose challenge are similar to young animals. Longitudinal assessments of MR and CF through 112 weeks of age reveal that MR prevents age-associated increases in serum lipids. By 16 weeks, MR animals show a 40% reduction in insulin-like growth factor-1 (IGF-1) that is sustained throughout life; CF IGF-1 levels decline much later, beginning at 112 weeks. Collectively, the results indicate that MR reduces visceral fat and preserves insulin activity in aging rats independent of energy restriction.

A fasting-mimicking diet, consisting of very low calorie and protein that leads to similar physiological response to fasting, including reduced levels of glucose and IGF-1 and increased levels of ketone bodies IGFBP-1, enhanced healthspan and rejuvenated the hematopoietic system while promoting adult neurogenesis :  Brandhorst S, Choi IY, Wei M, et al.: A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan. Cell Metab. 2015; 22(1): 86–99. 

Feeding schedule has also been shown to have a significant impact on health and survival. In flies, time-restricted feeding (limited to 12 daytime hours every day) had profound effects on neural, peripheral, and cardiovascular physiology and improved sleep, body weight maintenance, and delayed signs of cardiac aging, under unchanged caloric intake and activity.  Time-restricted feeding attenuates age-related cardiac decline in Drosophila  Abstract: Circadian clocks orchestrate periods of rest or activity and feeding or fasting over the course of a 24-hour day and maintain homeostasis. To assess whether a consolidated 24-hour cycle of feeding and fasting can sustain health, we explored the effect of time-restricted feeding (TRF; food access limited to daytime 12 hours every day) on neural, peripheral, and cardiovascular physiology in Drosophila melanogaster. We detected improved sleep, prevention of body weight gain, and deceleration of cardiac aging under TRF, even when caloric intake and activity were unchanged. We used temporal gene expression profiling and validation through classical genetics to identify the TCP-1 ring complex (TRiC) chaperonin, the mitochondrial electron transport chain complexes, and the circadian clock as pathways mediating the benefits of TRF.

When mice were given access to food for only 8–9 hours during the active phase of the day, metabolic diseases induced by a high-fat, high-fructose, and high-sucrose diet, were reduced without lowering caloric intake : Time restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high fat diet  Abstract: While diet-induced obesity has been exclusively attributed to increased caloric intake from fat, animals fed a high-fat diet (HFD) ad libitum (ad lib) eat frequently throughout day and night, disrupting the normal feeding cycle. To test whether obesity and metabolic diseases result from HFD or disruption of metabolic cycles, we subjected mice to either ad lib or time-restricted feeding (tRF) of a HFD for 8 hr per day. Mice under tRF consume equivalent calories from HFD as those with ad lib access yet are protected against obesity, hyperinsulinemia, hepatic steatosis, and inflammation and have improved motor coordination. The tRF regimen improved CREB, mTOR, and AMPK pathway function and oscillations of the circadian clock and their target genes’ expression. These changes in catabolic and anabolic pathways altered liver metabolome and improved nutrient utilization and energy expenditure. We demonstrate in mice that tRF regimen is a nonpharmacological strategy against obesity and associated diseases.

Ad lib feeding during the weekend did not interfere with the protective effects of time-restricted feeding: Time-Restricted Feeding Is a Preventative and Therapeutic Intervention against Diverse Nutritional Challenges Abstract:  Time-restricted feeding (TRF) confines food access to 9–12 hr during the active phase. TRF is a therapeutic intervention against obesity without calorie restriction.TRF protects against metabolic diseases even when briefly interrupted on weekends. TRF is effective against high-fat, high-fructose, and high-sucrose diets. Because current therapeutics for obesity are limited and only offer modest improvements, novel interventions are needed. Preventing obesity with time-restricted feeding (TRF; 8–9 hr food access in the active phase) is promising, yet its therapeutic applicability against preexisting obesity, diverse dietary conditions, and less stringent eating patterns is unknown. Here we tested TRF in mice under diverse nutritional challenges. We show that TRF attenuated metabolic diseases arising from a variety of obesogenic diets, and that benefits were proportional to the fasting duration. Furthermore, protective effects were maintained even when TRF was temporarily interrupted by ad libitum access to food during weekends, a regimen particularly relevant to human lifestyle. Finally, TRF stabilized and reversed the progression of metabolic diseases in mice with preexisting obesity and type II diabetes. We establish clinically relevant parameters of TRF for preventing and treating obesity and metabolic disorders, including type II diabetes, hepatic steatosis, and hypercholesterolemia.

A restricted feeding pattern reversed the progression of pre-existing obesity and type II diabetes, suggesting it has the potential to be a clinically relevant and feasible dietary intervention, useful to prevent and treat obesity and metabolic disorders : Time-Restricted Feeding Is a Preventative and Therapeutic Intervention against Diverse Nutritional Challenges

. Considering that key metabolic factors, such as 5’ AMP-activated protein kinase (AMPK), sirtuins, and protein kinase B (AKT), are regulated by an interplay of circadian rhythm and feeding time54,55, dietary schedules should be more carefully studied in the context of dietary restriction. Metabolism and the Circadian Clock Converge : Abstract: Circadian rhythms occur in almost all species and control vital aspects of our physiology, from sleeping and waking to neurotransmitter secretion and cellular metabolism. Epidemiological studies from recent decades have supported a unique role for circadian rhythm in metabolism. As evidenced by individuals working night or rotating shifts, but also by rodent models of circadian arrhythmia, disruption of the circadian cycle is strongly associated with metabolic imbalance. Some genetically engineered mouse models of circadian rhythmicity are obese and show hallmark signs of the metabolic syndrome. Whether these phenotypes are due to the loss of distinct circadian clock genes within a specific tissue versus the disruption of rhythmic physiological activities (such as eating and sleeping) remains a cynosure within the fields of chronobiology and metabolism. Becoming more apparent is that from metabolites to transcription factors, the circadian clock interfaces with metabolism in numerous ways that are essential for maintaining metabolic homeostasis. 

Time of feeding and the intrinsic circadian clock drive rhythms in hepatic gene expression Abstract: In mammals, the circadian oscillator generates approximately 24-h rhythms in feeding behavior, even under constant environmental conditions. Livers of mice held under constant darkness exhibit circadian rhythm in abundance in up to 15% of expressed transcripts. Therefore, oscillations in hepatic transcripts could be driven by rhythmic food intake or sustained by the hepatic circadian oscillator, or a combination of both. To address this question, we used distinct feeding and fasting paradigms on wild-type (WT) and circadian clock-deficient mice. We monitored temporal patterns of feeding and hepatic transcription. Both food availability and the temporal pattern of feeding determined the repertoire, phase, and amplitude of the circadian transcriptome in WT liver. In the absence of feeding, only a small subset of transcripts continued to express circadian patterns. Conversely, temporally restricted feeding restored rhythmic transcription of hundreds of genes in oscillator deficient mouse liver. Our findings show that both temporal pattern of food intake and the circadian clock drive rhythmic transcription, thereby highlighting temporal regulation of hepatic transcription as an emergent property of the circadian system.