The ketogenic diet (KD) has gained popularity as doctors and researchers investigate its potential benefits. Nutritional ketosis, the goal of ketogenic diets, is achieved by restricting carbohydrate intake, moderating protein consumption, and increasing fat intake. This restriction causes the body to switch from glucose metabolism to using ketone bodies from fat metabolism as its primary energy source. Recent studies of low-carbohydrate, high-fat (LCHF) diets, such as the ketogenic diet, show promise in helping patients lose weight, reverse metabolic syndrome, reduce or eliminate insulin requirements for type II diabetics, reduce inflammation, improve epigenetic profiles, alter the microbiome, improve lipid profiles, supplement cancer treatments, and potentially increase longevity and brain function.
The Ketogenic Diet: A Multifaceted Approach to Health
Given the lack of a comprehensive overview of the ketogenic diet (KD) in relation to health issues, evidence related to the use of the KD in relation to its impact on the microbiome, the epigenome, diabetes, weight loss, cardiovascular health, and cancer has been compiled.
- Microbiome: The KD diet could potentially increase the genetic diversity of the microbiome and increase the ratio of Bacteroidetes to Firmicutes.
- Epigenome: The epigenome might be positively affected by the KD since it creates a signaling molecule known as β-hydroxybutyrate (BHB).
- Diabetes: KD has helped patients with diabetes reduce their HbA1c and reduce the need for insulin.
- Weight Loss: There is evidence to suggest that a KD can help with weight loss, visceral adiposity, and appetite control.
- Cardiovascular Health: The evidence also suggests that eating a high-fat diet improves lipid profiles by lowering low-density lipoprotein (LDL), increasing high-density lipoprotein (HDL), and lowering triglycerides (TG).
- Cancer: Due to the Warburg effect, the KD is used as an adjuvant treatment to starve cancer cells, making them more vulnerable to chemotherapy and radiation.
The potential positive impacts of a KD on each of these areas warrant further analysis, improved studies, and well-designed randomized controlled trials to further illuminate the therapeutic possibilities provided by this dietary intervention.
The number of Americans suffering from obesity, diabetes, and metabolic syndrome is on the rise. Markers of metabolic syndrome include increased abdominal adiposity, insulin resistance, elevated triglycerides, and hypertension. These negative health markers increase the risk of cardiovascular disease, diabetes, stroke, and Alzheimer’s disease. Many researchers believe these diseases result from carbohydrate intolerance and insulin resistance. Thus, a diet that reduces exposure to carbohydrates, including whole grains, might be a more logical recommendation for improving health.
Types of Ketogenic Diets
Two dietary regimens, the standard ketogenic diet and the therapeutic ketogenic diet, restrict carbohydrate consumption to varying degrees and are being studied for their health impacts. The therapeutic ketogenic diet, which severely restricts both carbohydrates and protein, is typically used in the treatment of epilepsy and cancer. However, the Dietary Guidelines for Americans suggest that between 45 and 65% of caloric intake should come from carbohydrates.
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It is important to clarify the difference between a low-carb diet and a low-carb ketogenic diet (LCKD). Ketosis is normally achieved through either fasting or carbohydrate restriction. A low-carb diet typically refers to a diet with an intake of 50 to 150 g of carbohydrate per day. However, although this is a lower amount of carbohydrates than the standard American diet, it is not low enough to enter nutritional ketosis. Only when a patient restricts carbohydrates to less than 50 g/day will the body be incapable of fueling the body by glucose and will switch to burning fat.
The ketogenic diet is a reversal of the current food pyramid supported by the dietary guidelines. Thus, instead of a diet rich in carbohydrates, it is high in fat. The resulting carbohydrate restriction lowers blood glucose levels, and the subsequent insulin changes will instruct the body to change from a state of storing fat to a state of fat oxidation. Once fats are utilized as the primary fuel source in the liver, the production of ketone bodies begins, a process known as ketogenesis. During ketosis, three major ketone bodies are formed and utilized by the body for energy: acetone, acetoacetate, and β-hydroxybutyrate. All cells that contain mitochondria can meet their energy demands with ketone bodies, including the brain and muscle.
The Microbiome and the Ketogenic Diet
The microbiome consists of trillions of microscopic organisms in the human gastrointestinal tract, comprising over 8000 different types of bacteria, viruses, and fungi living in a complex ecosystem. Recent research suggests that the genetic make-up of a microbiome can be affected by lifestyle factors which include but are not limited to sleep, exercise, antibiotic use, and even diet. These bacteria can alter our response to different food sources because they differ in their ability to harvest energy from food, affecting the postprandial glucose response (PPGR).
The composition of the microbiome, which is believed to have a fundamental role in human health, is shaped predominantly by environmental factors. Research into the complex interactions that exist between diet, the microbiome, and host metabolic rates has increased. People eating processed and bland food had reduced diversity of their microbiota, while people eating a diet rich in fruit and vegetables had increased diversity in their gut microbiota. Gut biomes that lacked genetic diversity were related to overall adiposity, insulin resistance, dyslipidemia, and an inflammatory phenotype.
Discovering how the gut microbiota and diet interact and how this interaction is connected to overall health, is critical. It is important to determine whether new dietary changes, such as a ketogenic diet, will positively or negatively affect overall microbiome diversity and species make-up. Some research has found that whole grains play an important role in the development of a healthy microbiome and are necessary for good health. Thus, a person consuming a ketogenic diet might not consume enough whole grains to maintain a healthy microbiome. Low-carb diets are at greater risk of being nutritionally inadequate by lacking in fiber, necessary vitamins, minerals, and iron. Thus, it is even more critical that people on a LCKD choose desirable low carbohydrate foods that are rich in fiber. In addition, a ketogenic diet should maintain moderate protein intake of around 1.5 g/day per kg of respective body weight.
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Currently, scientists do not have any data on the long-term effects of the ketogenic diet on the gut microbiome. Based on various studies, many predict that the diet will positively affect the microbiome by increasing the Bacteroidetes and Bifidobacteria species associated with improved health and decreasing microbial species known to increase health risks. In fact, a study found that the disrupted gut microbiota of epileptic infants was improved with a one-week ketogenic diet, which managed to increase their Bacteroides amount by ~24%. Studies have shown that a low ratio of Firmicutes to Bacteroidetes is an indicator of a healthy microbiome. A few studies found that obese patients were more likely to have a higher Firmicutes to Bacteroidetes ratio and higher levels of short chain fatty acids (SCFAs) in their stool. Therefore, it appears that reducing obesity with the KD may result in positive changes in the microbiome.
Recently, a few short-term studies tested the impact of the KD on patient microbiomes. A study analyzed the effect of a modified Mediterranean Ketogenic Diet (MMKD) vs. the American Heart Association Diet (AHAD) on the microbiome of patients with normal cognition or mild cognitive impairment. They found that the MMKD did not show significant changes in the Firmicutes or Bacteroides phyla at 6 weeks. However, they did see a decrease in the family Bifidobacteriaceae and an increase in family Verrucomicrobiaceae, which was considered a positive change. Furthermore, the beneficial SCFA, butyrate, increased in the MMKD. The presence of butyrate has been known to increase gut health.
Epigenetics and the Ketogenic Diet
Epigenetics refers specifically to changes “on top” of the genome that can modify and alter levels of gene expression. These epigenetic markers are heritable, yet recent research suggests that some changes can be reversed or occur through environmental changes. The modifications of the genome involve DNA methylation, changes to chromatin structure, histone modification, and noncoding RNAs.
Some ketogenic food sources that positively regulate epigenetic activity are cruciferous vegetables, dietary fiber, foods rich in long-chain fatty acids, and berries, such as raspberries. The benefits of some of these food sources have a multitude of positive effects. For instance, black raspberries not only positively affect methylation patterns in the WNT-signaling pathway, but they also profoundly impact the microbiome make-up (increased Lactobacillus, Bacteroidaceae, and anti-inflammatory bacterial species), and increased production of butyrate by fermentation in the gut.
The benefits of the ketogenic diet might also go beyond treating existing disease, and instead help prevent chronic and degenerative disease. A literature review argued that a state of nutritional ketosis will positively affect mitochondrial function and enhance resistance to oxidative stress and noted that the ketones directly up-regulate bioenergetic proteins that influence antioxidant defenses.
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Ribose: A Closer Look
Ribose (D-ribose) is a natural, simple sugar used as a dietary supplement. It may speed exercise recovery, help with heart conditions, and smooth wrinkles. But with few studies, it's still unclear if ribose can be of much help.
There are two forms of the sugar ribose: L-ribose and D-ribose. L-ribose is man-made (nonnatural), but your body makes D-ribose. Your cells use the simple sugar to make RNA, DNA, and adenosine triphosphate (ATP). ATP supplies energy to your cells. You can also find small amounts of the sugar in ripe fruits and veggies.
People may take ribose for many reasons. It's still unclear if the supplement is useful. But companies claim it can help you:
- Increase endurance and energy
- Reduce muscle fatigue
- Speed up post-workout recovery
- Improve certain heart conditions
- Smooth wrinkles on your skin
As you move, your muscles break ATP down to obtain energy. With high-intensity exercise, the ATP gets used up, but your body can replace it using ribose.
Some studies suggest the supplement can speed post-workout recovery. But this sugar doesn't always boost exercise performance. Many studies tested ribose on high-intensity exercise such as cycle sprints. And not many studies look at strength or endurance. Without quality studies, it's unclear if supplements can help your sport performance.
Ribose may provide energy for heart cells. Some limited studies suggest it helps after a heart attack or angina episode. But without more studies, it's unknown if ribose helps.
As your skin ages, your cells lose ATP and energy. Some companies promote this sugar in skincare products. Adding it to facial lotion may help restore ATP to your skin.
This simple sugar is naturally found in all living cells. You can find small amounts of ribose in brewer's yeast, ripe fruit, and ripe vegetables. But there's not enough to raise your levels. That's because it's in material form such as ATP, DNA, and RNA. The small amount that's free is likely destroyed after cooking. To reach the amounts used in studies, you'll need to take a supplement.
Potential Benefits of Ribose
If you take the supplement, you may notice:
- Less muscle soreness and fatigue after your exercise
- Better exercise performance and faster post-workout recovery
- Improved heart function for people with certain heart conditions or angina
- Higher exercise ability after your heart attack or angina episode
- More collagen and skin elasticity to reduce your wrinkles (but more studies are needed on this)
And a few case studies show more energy with ribose. But it's still unclear how the supplement helps chronic fatigue. Most studies about the benefits come from lower ATP levels. Either a medical condition or exercise lowered the cell's ATP level.
Risks and Considerations
If you take the supplement, you may have higher risk for:
- Headaches
- Upset stomach
- Diarrhea
- Higher uric acid in your blood and urine
But long-term safety studies haven't been done. The FDA doesn't check dietary supplements as it examines a medicine. This is made as a food supplement. This means the company only has to show the supplement is generally recognized as safe (GRAS). There isn't a standard supplement dose, but the European Food Safety Authority (EFSA) suggests no more than 10 grams a day.
Who Should Avoid Ribose?
You may want to avoid the supplement if you:
- Are pregnant or breastfeeding (chestfeeding)
- Have type 1 or type 2 diabetes
- Take diabetes medication, as it may lower your blood sugar
- Have prediabetes
- Are scheduled for surgery (at least two weeks before)
Your cells can use glucose to make ribose if you're low on it. Then, your cells convert it to ATP for energy. But if you take extra, the simple sugar can build up. The supplement can flood your cells, and the extra sugar can damage the cells. Experts don't agree, but higher ribose may cause more inflammation. Studies show higher levels in people with diabetes may be linked to higher HbA1c, too.
Always talk to your doctor about any supplements you're taking. They can explain any side effects or possible medication interactions.
Ribose is a simple sugar sold as a dietary supplement to boost muscle cell energy. The supplement may help speed up post-exercise recovery and ease certain symptoms of heart conditions. But it's still unclear how this simple sugar works or if it offers benefits. Talk to your doctor before taking the supplement, especially if you have diabetes so you can make sure it's safe for you.
Ribose and Specific Health Conditions
- Diabetes: D-ribose may not be safe for people with diabetes. If you have diabetes, you should avoid the supplement. It's still not clear, but the sugar may complicate diabetes and raise HbA1c. And with diabetes medicine, ribose may also lower your blood sugar (hypoglycemia).
- Heart Health: Some studies show the supplement can help with certain heart problems. But other studies were unclear. Talk with your doctor before taking any supplements to find out what's safe for your heart health.
- Liver Health: It's not clear how this supplement impacts your liver. Some animal studies suggest abnormal liver tests after using D-ribose. But studies in athletes showed no changes in liver function after two weeks of taking supplements.
- Kidney Health: Studies are limited on the link between kidney problems and ribose.
- Skin Health: Some skincare companies claim this sugar helps your skin. One study showed about 12% reduced wrinkles after 14 days of using a lotion with the supplement. But after 28 days, no changes were seen. Some studies mention acne as a side effect.
Ribose in the Body
Ribose plays a crucial role in cellular energy production by serving as a key component of ATP, the primary energy currency of cells. In a study involving participants in an intensive cycling sprint program, those who took D-ribose maintained normal ATP levels, while the placebo group experienced a decrease in ATP.
A study found that D-ribose supplementation reduced muscle soreness and improved recovery from muscle damage in young adult males performing plyometric exercise. Research also has shown that D-ribose supplementation may be particularly beneficial for less trained individuals. While these findings are promising, it’s important to note that results have been mixed, particularly regarding athletic performance in highly trained individuals.
Ribose in Food and Supplementation
It can be difficult to get enough ribose from dietary sources. This natural sugar is available in health stores and online in supplement form as a powder, chewable tablet or capsule.
When considering ribose supplementation, it is important to be aware of potential drug interactions, particularly with insulin and other anti-diabetes drugs.
Concerns Regarding Ribose Supplementation
Reports concerning the beneficial effects of D-ribose administration in cardiovascular and muscle stressful conditions has led to suggestions for the use of ribose as an energizing food supplement for healthy people. However, this practice still presents too many critical issues, suggesting that caution is needed. In fact, there are many possible negative effects of this sugar that are underestimated, if not neglected, by the literature supporting the presentation of the product to the market. The risks deriving from the use of free ribose as ATP source, forcing ribose-5-phosphate to enter into the pentose phosphate pathway, is emphasized.
Ribose and Nucleotide Synthesis
We are so used to seeing the ribose scaffold in relevant biological molecules as nucleotides and nucleic acids that not thinking that D-ribose enters as a precursor of their synthesis will sound almost inconceivable. However, it seems that such an apparent “ready to use” precursor for nucleotide synthesis is mainly disregarded in the metabolic implant, being glucose, through its phosphorylation at C6, the preferred precursor of the ribofuranosidic scaffold of nucleotides. Nevertheless, D-ribose intake has been proposed as a strategic approach to increase levels of ATP.
The Commercialization of Ribose
If we simply consider the widespread “commercial propaganda” about the beneficial effects of D-ribose in the human metabolism, we may be convinced that this metabolite is essential for an energy-filled, healthy, and enjoyable life. Emphasis on this aspect appears in many commercial advertisements, highlighting the fact that ribose, being part of nucleotides, has the potential to enhance ATP availability. Thus, ribose intake is suggested to energize healthy subjects undergoing physical exercise. However, with a basic insight into metabolic processes, it is not difficult to challenge the commercial presentation of this “fantastic” food integrator, even if allegedly supported by literature references. The main concern arising from many of these presentations is related to the ambiguity on the goal of the proposed treatment and the inadequacy in presenting what we can define as the “unfriendly features” of ribose. In fact, it is rather ambiguous whether ribose intake should improve the energy charge or the nucleotide pool level or both. On the other hand, the possible adverse effects linked to the reactivity of the ribose molecule are essentially neglected. Thus, the energy injection that should occur in healthy active people (children, runners, body builders, sportsmen), deriving from D-ribose, doesn’t have, yet, any strong scientific base allowing the proposal and promotion for indiscriminate consumption of the sugar. Conversely, the risk of damage arising from circulating ribose is firmly standing.
As potential customers rather than as scientists, there is worry in learning of the actions undertaken by ribose Producers at the level of European Commission to advocate for the integration of this molecule in the formulations of a variety of edible products, from energy bars and drinks, to biscuits, flavored drinks, fruit juice, vegetable juice, and yogurt.
Ribose vs. Glucose
Due to the structural unreliability of ribose and due to its the remarkable glycation ability, this sugar should have appeared ab initio too risky in supporting a relevant goal as the nucleotide synthesis. Then, the pentose phosphate pathway (PPP), jointly to its function of replenishment of reducing equivalents (i.e., NADPH formation), is widely recognized as the mainstream of ribose-5-phosphate (R5P) synthesis, through the use of glucose-6 phosphate as precursor. This unavoidable precursor of de novo nucleotide synthesis is an intermediate of the reversible reaction network of PPP. These reactions modulate the overall PPP by recycling the C3 to C6 glucose-derived carbon atoms into the main glycolytic/gluconeogenic flux.
R5P would also directly enter PPP by the ATP dependent phosphorylation of D-ribose catalyzed by ribokinase (RK). This enzyme, which belongs to the PfkB family of carbohydrate kinases has been characterized in human and displays most of the features of the E. coli RK in terms of phosphate and metal ion activation. Nevertheless, the human enzyme exhibits a reduced efficiency with respect to bacterial RK, with KM values for D-ribose of at least one order of magnitude higher (approximately 2 mM versus 0.2 mM). Furthermore, a substrate inhibition by ribose is observed, which may limit R5P formation.
Much more evident is the lack of efficiency of RK when compared to adenosine kinase (AdoK), another member of the PfkB carbohydrate kinase family. This enzyme shares with RK structural elements, regulatory properties, and the ability to recognize as substrate the C5-hydroxyl group of the ribofuranoside scaffold (here linked to the purine base). The KM value of the human AdoK for adenosine is in the range of µM or sub-µM levels (0.1 to 3 µM), from two to three order of magnitude lower than of RK for D-ribose. Besides possible peculiar differences between these strongly related family members, the poor effectiveness of RK may certainly be ascribed to the unreliability of the D-ribose, mostly present in solution in its pyranosidic form (80%), which is less adequate as substrate for RK action. In any case, R5P may eventually be formed upon RK action. This is the route invoked by ribose “supporters” to rationalize the beneficial features of exogenously supplemented ribose entering the glycolytic/gluconeogenic pathway and, most importantly, the nucleotides synthesis. In this regard it is worth noting that the need of this ATP-dependent activation step for ribose to enter metabolic routes excludes any possible advantage of ribose with respect to glucose as ergogenic nutrient. On the other hand, with some exceptions, ribose alone is unable to sustain cell growth.
Ergogenic Effects of Ribose
The ergogenic effect of ribose comes out from studies in which the ability of the cell to warrant the homeostasis of ATP is somehow compromised. This is due to either a pathological status or an excessive energy expenditure. Evidence has been reported from studies on animals and humans for which ribose treatment may be helpful in cardiovascular diseases. An increase in the rate of ATP recovery in myocardium after ribose intravenous injection was observed in rats undergoing oxygen reperfusion after myocardial ischemia. A similar effect was reported in a canine model for myocardial ischemia, in which the level of ATP, accounting for 50% of the pre-ischemic level, was restored after 24 h to 85% in animals subjected to ribose infusion. D-ribose intake was successfully used to ameliorate symptoms in the case of fibromyalgia and chronic fatigue syndrome. In a case report of a patient affected by myoadenilate deaminase deficiency, a recovery of ATP depletion was observed after ribose treatment.
With such evidence, the rational base of the reports claiming the beneficial effect of an external supplement of ribose generally referred to a failure of the oxidative branch of PPP, unable anymore to replenish R5P levels adequate for the de novo synthesis and “salvage” of nucleotides. The benefits that ribose may offer in a number of pathological situations has been exhaustively reviewed. However, no research has been carried out regarding some problems that the ribose treatment may, at least theoretically, promote.
Besides some attempts tailored to verify the potential usefulness of ribose intake to ameliorate the distress in pathological conditions, ribose treatment was widely tested to prove the advantages it could have for healthy people to ameliorate their physical performance. There is evidence that the rate enhancement, if any, of ATP resynthesis occurring after repeated physical exercise does not imply any improvement in the performance score. However, a number of reports on healthy subjects underline the advantage of taking ribose. It is in this literature frame that the idea to administer ribose to healthy people as energizer emerged, giving the scientific support for commercial spots to include ribose as a dietary integrator.