When our cells undergo the process of autophagy, non-essential parts like damaged proteins are recycled and invading microorganisms and toxic compounds are removed. This means that autophagy plays an important role in stopping the aging process, reversing disease, and preventing cancer, but it doesn’t happen all the time. Fasting, protein restriction, and carbohydrate restriction are the three main ways that can initiate different autophagic processes — all of which are not the same. This is part of the reason why a ketogenic diet has so many positive effects, and it also shows you why intermittent fasting is a way to improve your diet even more.
Exogenous ketones have a wide range of benefits that can enhance your fat-burning lifestyle. I personally use them daily as a strategy to heighten my mental performance and give my workouts an extra boost. For these purposes, I have also found it logical to combine exogenous ketones with other known health and performance boosting agents such as branched-chain amino acids and medicinal mushrooms.
Some people follow more of an Ultra Low Carb diet approach. This is generally around 50g or less of carbs per day. A ULC is more supportive of reaching a ketogenic state, but again total carbs are not the only variable when it comes to reaching ketosis (other factors such as types of carbs, protein consumption, portion size, ingredients, supplements used etc. all play a role and will be covered in more detail below).
Over the 28-day experiment, ketone supplements administered daily significantly elevated blood ketone levels without dietary restriction (Fig. 2a, b). Naturally derived ketogenic supplements including MCT (5 g/kg) elicited a significant rapid elevation in blood βHB within 30–60 min that was sustained for 8 h. BMS + MCT (5 g/kg) elicited a significant elevation in blood βHB at 4 h, which was no longer significant at 8 h. BMS (5 g/kg) did not elicit a significant elevation in blood βHB at any time point. For days 14–28, BMS + MCT (10 g/kg) and MCT (10 g/kg) elevated blood βHB levels within 30 min and remained significantly elevated for up to 12 h. We observed a delay in the peak elevation of blood βHB: BMS + MCT peaked at 8 h instead of at 4 h and MCT at 4 h instead of at 1 h. Blood βHB levels in the BMS group did not show significant elevation at any time point, even after dose escalation (Fig. 2a). Synthetically derived ketogenic supplements including KE and BD supplementation rapidly elevated blood βHB within 30 min and was sustained for 8 h. For the rats receiving ketone supplementation in the form of BD or the KE, dosage was kept at 5 g/kg to prevent adverse effects associated with hyperketonemia. The Precision Xtra™ ketone monitoring system measures βHB only; therefore, total blood ketone levels (βHB + AcAc) would be higher than measured. For each of these groups, the blood βHB profile remained consistent following daily ketone supplementation administration over the 4-week duration. (Fig. 2b).
Weight loss benefits ushered the keto diet into the spotlight. That’s how most people have likely heard about ketones, a fuel source created naturally by the body when burning fat. But more and more research points to diverse applications of ketones in the blood outside of just fat loss, from improved endurance performance to the treatment of medical conditions like epilepsy.
On day 29, rats were sacrificed via deep isoflurane anesthesia, exsanguination by cardiac puncture, and decapitation 4–8 h after intragastric gavage, which correlated to the time range where the most significantly elevated blood βHB levels were observed. Brain, lungs, liver, kidneys, spleen and heart were harvested, weighed (AWS-1000 1 kg portable digital scale (AWS, Charleston, SC)), and flash-frozen in liquid nitrogen or preserved in 4 % paraformaldehyde for future analysis.
The other potentially important distinction between nutritional ketosis and chemically-induced ketosis is the potential metabolic role played by liver AcAc production and redox status. Although the ratio of BOHB to AcAc in venous blood is typically 80% to 20%, classic studies by Cahill (1975) have observed important hepatic vein and peripheral arterio-venous gradients for this ratio in keto-adapted patients. What these observations imply is that the liver produces a higher proportion of AcAc than is found in the peripheral blood, and that this is due to uptake of AcAc in peripheral cells (principally muscle) with re-release as BOHB. In the process, the reduction of AcAc to BOHB produces NAD+, which is beneficial to mitochondrial redox state and mitochondrial function (Verdin 2015, Newman 2017).
Effects of beta-hydroxybutyrate on cognition in memory-impaired adults. – Glucose is the brain’s principal energy substrate. In Alzheimer’s disease (AD), there appears to be a pathological decrease in the brain’s ability to use glucose. Neurobiological evidence suggests that ketone bodies are an effective alternative energy substrate for the brain. Elevation of plasma ketone body levels through an oral dose of medium chain triglycerides (MCTs) may improve cognitive functioning in older adults with memory disorders. On separate days, 20 subjects with AD or mild cognitive impairment consumed a drink containing emulsified MCTs or placebo. Significant increases in levels of the ketone body beta-hydroxybutyrate (beta-OHB) were observed 90 min after treatment (P=0.007) when cognitive tests were administered. beta-OHB elevations were moderated by apolipoprotein E (APOE) genotype (P=0.036). For 4+ subjects, beta-OHB levels continued to rise between the 90 and 120 min blood draws in the treatment condition, while the beta-OHB levels of 4- subjects held constant (P<0.009). On cognitive testing, MCT treatment facilitated performance on the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog) for 4- subjects, but not for 4+ subjects (P=0.04). Higher ketone values were associated with greater improvement in paragraph recall with MCT treatment relative to placebo across all subjects (P=0.02). Additional research is warranted to determine the therapeutic benefits of MCTs for patients with AD and how APOE-4 status may mediate beta-OHB efficacy. (http://www.ncbi.nlm.nih.gov/pubmed/15123336)
The blood levels of BOHB that can be achieved with the salts or ester formulations are in the 1-3 mM range, similar to what can be achieved with a well-formulated ketogenic diet in insulin sensitive humans, but well below levels achieved after a 4-7 days of total fasting (Owen 1969). In more insulin resistant humans, the ester formulation may deliver higher blood levels than a sustainable diet (as opposed to short term fasting). For example, in the Virta IUH Study of over 200 patients with type 2 diabetes, blood ketone mean levels were 0.6 mM at 10 weeks and 0.4 mM after 1 year.
Ketosis is a natural process that more and more people are flocking to these days in an effort to stay fit and healthy. Studies show that it has a host of health benefits and plays a key role in maintaining or changing your physical appearance by helping you lose weight. This is due to the fact that when the body is in a state of ketosis, it converts fat into compounds known as ketones, effectively turning fat into a source of energy.
Administration of ketone supplementation significantly reduced blood glucose over the course of the study (Fig. 3a, b). MCT (5 g/kg) decreased blood glucose compared to control within 30 min which was sustained for 8 h at baseline and at week 1. MCT (10 g/kg) likewise decreased blood glucose within 30 min and lasted through the 12 h time point during weeks 2, 3, and 4. BMS + MCT (5 g/kg) lowered blood glucose compared to control from hours 1–8 only at week 1. BMS + MCT (10 g/kg) lowered blood glucose compared to control within 30 min and remained low through the 12 h time point at weeks 2, 3, and 4. Rats supplemented with BMS had lower blood glucose compared to control at 12 h in week 4 (10) (Fig. 3a). Administration of BD did not significantly change blood glucose levels at any time point during the 4-week study. KE (5 g/kg) significantly lowered blood glucose levels at 30 min for week 1, 2, 3, and 4 and was sustained through 1 h at weeks 2–4 and sustained to 4 h at week 3. (Fig. 3b).
If you have already mastered the Very Low Carbohydrate (VLC) or ketogenic way of eating, and/or are eating at a caloric deficit, exercising or fasting you are naturally creating the optimal conditions for your body to produce ketones and put your body into nutritional ketosis. By strict adherence to a well-formulated ketogenic diet (complete with higher levels of mineral salts) you should be able to produce all the ketones you need naturally (endogenously). If you are new or inexperienced in ketogenic eating however; or if you or a family member struggles to adhere to a ketogenic diet, then supplementation with exogenous ketones may be very beneficial. Not only will ketone supplements help to mitigate hunger and carb cravings, but they will also help you stave off carb flu symptoms (see below), giving you the best possible chance of long-term success.
Over five visits, participants (n = 16) consumed either 4.4 mmol.kg−1 of βHB (2.2 mmol.kg−1 or 395 mg/kg of KE; 1 mole of KE delivered 2 moles of d-βHB equivalents): twice whilst fasted, and twice following a standardized meal, or an isocaloric dextrose drink without a meal. To improve palatability, drinks were diluted to 500 ml with a commercially available, citrus flavored drink containing 65 kCal (5 g of carbohydrate) (Glaceau, UK). The dextrose drink was taste-matched using a bitterness additive (Symrise, Holzminden, Germany). The standard meal consisted of porridge oats (54 g), semi-skimmed milk (360 ml) and banana (120 g), giving 600 kCal per person, with a macronutrient ratio of Carbohydrate: Protein: Fat of 2:1:1.
The difference in peak blood d-βHB concentrations between matched amounts of βHB as ester or salts arose because the salt contained l-βHB, as the blood concentrations of d- plus l-βHB isoforms were similar for both compounds. It is unclear if kinetic parameters of KE and KS drinks would be similar if matched d-βHB were taken in the drinks. Unlike d-βHB, blood l-βHB remained elevated for at least 8 h following the drink, suggesting an overall lower rate of metabolism of l-βHB as urinary elimination of l-βHB was in proportion to plasma concentration. Despite similar concentrations of total βHB, breath acetone was ~50% lower following KS drinks compared to KE, suggesting fundamental differences in the metabolic fates of D- and L-βHB. These findings support both previous hypotheses (Veech and King, 2016) and experimental work in rats (Webber and Edmond, 1977), which suggested that the l-isoform was less readily oxidized than the d-isoform, and is processed via different pathways, perhaps in different cellular compartments. It seems that l-βHB is not a major oxidative fuel at rest, and may accumulate with repeated KS drinks. However, the putative signaling role of l-βHB in humans remains unclear. In rodent cardiomyocytes, l-βHB acts as a signal that modulates the metabolism of d-βHB and glucose, Tsai et al. (2006) although no differences in blood glucose were seen here. Furthermore, L-βHB can act as a cellular antioxidant, although to a lesser extent than D-βHB (Haces et al., 2008).
Ketogenic Diets and Physical Performance – Impaired physical performance is a common but not obligate result of a low carbohydrate diet. Lessons from traditional Inuit culture indicate that time for adaptation, optimized sodium and potassium nutriture, and constraint of protein to 15–25 % of daily energy expenditure allow unimpaired endurance performance despite nutritional ketosis.
That said, there also remains the question of the relative benefits of AcAc versus BOHB, both as independent signaling molecules and as redox modulators in peripheral (aka non-hepatic) tissues. Seen from this perspective, AcAc generated in the liver acts as a NAD+ donor for the periphery, whereas pure BOHB taken orally, to the extent that it is retro-converted to AcAc (Sherwin 1975), potentially deprives the periphery of NAD+.
I’m getting an increasing number of questions about exogenous ketones. Are they good? Do they work for performance? Is there a dose-response curve? If I’m fasting, can I consume them without “breaking” the fast? Am I in ketosis if my liver isn’t producing ketones, but my BOHB is 1.5 mmol/L after ingesting ketones? Can they “ramp-up” ketogenesis? Are they a “smart drug?” What happens if someone has high levels of both glucose and ketones? Are some products better than others? Salts vs esters? BHB vs AcAc? Can taking exogenous ketones reduce endogenous production on a ketogenic diet? What’s the difference between racemic mixtures, D-form, and L-form? What’s your experience with MCTs and C8?
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